Fluorinated estrogen receptor modulators and uses thereof

ABSTRACT

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well as methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. §371 as a United StatesNational Phase Application of International Application No.PCT/US2012/069933, entitled “FLUORINATED ESTROGEN RECEPTOR MODULATORSAND USES THEREOF” filed on Dec. 14, 2012, which claims the benefit ofU.S. provisional patent application No. 61/570,756 entitled “ESTROGENRECEPTOR MODULATORS AND USES THEREOF” filed on Dec. 14, 2011, all ofwhich are incorporated by reference in their entirety.

FIELD OF THE INVENTION

Described herein are compounds, including pharmaceutically acceptablesalts, solvates, metabolites, prodrugs thereof, methods of making suchcompounds, pharmaceutical compositions comprising such compounds, andmethods of using such compounds to treat, prevent or diagnose diseasesor conditions that are estrogen sensitive, estrogen receptor dependentor estrogen receptor mediated.

BACKGROUND OF THE INVENTION

The estrogen receptor (“ER”) is a ligand-activated transcriptionalregulatory protein that mediates induction of a variety of biologicaleffects through its interaction with endogenous estrogens. Endogenousestrogens include 17β-estradiol and estrones. ER has been found to havetwo isoforms, ER-α and ER-β.

Estrogens and estrogen receptors are implicated in a number of diseasesor conditions, such as breast cancer, lung cancer, ovarian cancer, coloncancer, prostate cancer, endometrial cancer, uterine cancer, as well asothers diseases or conditions.

SUMMARY OF THE INVENTION

In one aspect, presented herein are compounds of Formula (I), (II),(III), (IV), (V), and (VI) that diminish the effects of estrogens withestrogen receptors and/or lower the concentrations of estrogenreceptors, and therefore, are useful as agents for the treatment orprevention of diseases or conditions in which the actions of estrogensand/or estrogen receptors are involved in the etiology or pathology ofthe disease or condition or contribute to at least one symptom of thedisease or condition and wherein such actions of estrogens and/orestrogen receptors are undesirable. In some embodiments, compoundsdisclosed herein are estrogen receptor degrader compounds.

In one aspect, a compound of Formula (I), (II), (III), (IV), (V), or(VI) is useful for the treatment of ER-related diseases or conditionsincluding, but not limited to, ER-α dysfunction associated with cancer(bone cancer, breast cancer, lung cancer, colorectal cancer, endometrialcancer, prostate cancer, ovarian and uterine cancer), central nervoussystem (CNS) defects (alcoholism, migraine), cardiovascular systemdefects (aortic aneurysm, susceptibility to myocardial infarction,aortic valve sclerosis, cardiovascular disease, coronary artery disease,hypertension), hematological system defects (deep vein thrombosis),immune and inflammation diseases (Graves' Disease, arthritis, multiplesclerosis, cirrhosis), susceptibility to infection (hepatitis B, chronicliver disease), metabolic defects (bone density, cholestasis,hypospadias, obesity, osteoarthritis, osteopenia, osteoporosis),neurological defects (Alzheimer's disease, Parkinson's disease,migraine, vertigo), psychiatric defects (anorexia nervosa, attentiondeficity hyperactivity disorder (ADHD), dementia, major depressivedisorder, psychosis), uterine diseases (e.g. leiomyoma, uterineleiomyoma, endometrial hyperplasia, endometriosis), and reproductivedefects (age of menarche, endometriosis, infertility).

In one aspect, described herein are compounds of Formula (I), (II),(III), (IV), (V), and (VI), pharmaceutically acceptable salts, solvates,metabolites and prodrugs thereof. Compounds described herein areestrogen receptor modulators. In some embodiments, the compound ofFormula (I), (II), (III), (IV), (V), or (VI) is an estrogen receptorantagonist. In some embodiments, the compound of Formula (I), (II),(III), (IV), (V), or (VI) is an estrogen receptor degrader. In someembodiments, the compound of Formula (I), (II), (III), (IV), (V), or(VI) is an estrogen receptor antagonist as well as an estrogen receptordegrader. In some embodiments, the compound of Formula (I), (II), (III),(IV), (V), or (VI) displays minimal or no estrogen receptor agonistactivity. In some embodiments, in the context of treating cancers, thecompound of Formula (I), (II), (III), (IV), (V), or (VI) may offerimproved therapeutic activity characterized by complete orlonger-lasting tumor regression, a lower incidence or rate ofdevelopment of resistance to treatment, and/or a reduction in tumorinvasiveness.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₁₀ heterocycloalkyl;        -   each R²³ is independently F or C₁-C₆-fluoroalkyl;        -   t is 1, 2, 3, or 4;    -   R⁴ is H, halogen, —CN, C₁-C₄alkyl, C₁-C₄-fluoroalkyl or        C₃-C₆cycloalkyl;    -   R⁵ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,        C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   each R⁶ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   R⁷ is H or C₁-C₄alkyl;    -   each R⁸ is independently selected from H, halogen, —CN, —OH,        C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, and        C₁-C₆alkoxy;    -   each R¹⁰ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R¹¹ is independently selected from H, —C(═O)R¹²,        —C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl,        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹² is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2;    -   provided that the compound is not        2-(4-((S)-2-(R)-3-fluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol.

For any and all of the embodiments described herein, substituents areselected from among a subset of the listed alternatives. For example insome embodiments, R⁷ is H or —CH₃. In other embodiments, R⁷ is H.

In some embodiments, R¹ is H or C₁-C₆alkyl; R² is H, C₁-C₆alkyl, orC₁-C₆-fluoroalkyl; R³ is C₁-C₆-fluoroalkyl; or R² and R³ are takentogether with the N atom to which they are attached to form

is a 4-, 5-, 6- or 7-membered monocyclic C₂-C₆heterocycloalkyl; each R²³is independently F or C₁-C₆-fluoroalkyl; t is 1 or 2; R⁴ is —CH₃; R⁷ isH; p is 0 or 1.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, R⁵ is —OH; each R¹⁰ is independently selected fromH, halogen, —CN, —OH, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R¹¹ is H.

In some embodiments, R¹ is H, or —CH₃; R² and R³ are taken together withthe N atom to which they are attached to form

is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, orpiperazinyl; each R²³ is independently F, —CH₂F, —CHF₂, —CF₃, —CHFCH₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃,—CH(CF₃)₂, or —CF(CH₃)₂.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments,

In another aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   R¹ is C₁-C₆-fluoroalkyl;

-   -    is a monocyclic C₂-C₁₀heterocycloalkyl;        -   each R²³ is independently F, C₁-C₆alkyl or            C₁-C₆-fluoroalkyl;        -   t is 0, 1, 2, 3, or 4;    -   R⁴ is H, halogen, —CN, C₁-C₄alkyl, C₁-C₄-fluoroalkyl or        C₃-C₆cycloalkyl;    -   R⁵ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,        C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   each R⁶ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R⁸ is independently selected from H, halogen, —CN, —OH,        C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, and        C₁-C₆alkoxy;    -   each R¹⁰ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R¹¹ is independently selected from H, —C(═O)R¹²,        —C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl,        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹² is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2.

In some embodiments, R¹ is —CH₂F, —CHF₂, or —CF₃;

is an azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl; each R²³ isindependently F, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or—CF(CH₃)₂; t is 0, 1 or 2; R⁴ is —CH₃; R⁷ is H; p is 0 or 1.

In some embodiments, the compound has one of the following structures:

In some embodiments, R⁵ is —OH; each R¹⁰ is independently selected fromH, halogen, —CN, —OH, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R¹¹ is H.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, each R²³ is independently F, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂. In some embodiments,each R²³ is independently F, —CH₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently F, —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently —CH₃, —CH₂F, —CHF₂, or —CF₃. Insome embodiments, each R²³ is independently —CH₃.

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form substituted or unsubstitutedpyrrolidinyl.

In some embodiments, R¹ is —CH₃. In some embodiments, R¹ is —CH₃; R⁴ is—CH₃.

Compounds disclosed herein are estrogen receptor modulators. In someembodiments, compounds disclosed herein have high specificity for theestrogen receptor and have desirable, tissue-selective pharmacologicalactivities. Desirable, tissue-selective pharmacological activitiesinclude, but are not limited to, ER antagonist activity in breast cellsand no ER agonist activity in uterine cells. In some embodiments,compounds disclosed herein are estrogen receptor degraders that displayfull estrogen receptor antagonist activity with negligible or minimalestrogen receptor agonist activity.

In some embodiments, compounds disclosed herein are estrogen receptordegraders. In some embodiments, compounds disclosed herein are estrogenreceptor antagonists. In some embodiments, compounds disclosed hereinhave minimal or negligible estrogen receptor agonist activity.

In some embodiments, presented herein are compounds selected from activemetabolites, tautomers, pharmaceutically acceptable solvates,pharmaceutically acceptable salts or prodrugs of a compound of Formula(I), (II), (III), (IV), (V), or (VI).

Also described are pharmaceutical compositions comprising atherapeutically effective amount of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof. In some embodiments, the pharmaceutical composition alsocontains at least one pharmaceutically acceptable inactive ingredient.In some embodiments, the pharmaceutical composition is formulated forintravenous injection, subcutaneous injection, oral administration, ortopical administration. In some embodiments, the pharmaceuticalcomposition is a tablet, a pill, a capsule, a liquid, a suspension, agel, a dispersion, a suspension, a solution, an emulsion, an ointment,or a lotion.

In some embodiments, the pharmaceutical composition further comprisesone or more additional therapeutically active agents selected from:corticosteroids, anti-emetic agents, analgesics, anti-cancer agents,anti-inflammatories, kinase inhibitors, antibodies, HSP90 inhibitors,histone deacetylase (HDAC) inhibitors, poly ADP-ribose polymerase (PARP)inhibitors, and aromatase inhibitors.

In some embodiments, provided herein is a method comprisingadministering a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, to a human with adiseases or condition that is estrogen sensitive, estrogen receptormeditated or estrogen receptor dependent. In some embodiments, the humanis already being administered one or more additional therapeuticallyactive agents other than a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof. In someembodiments, the method further comprises administering one or moreadditional therapeutically active agents other than a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof.

In some embodiments, the one or more additional therapeutically activeagents other than a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, are selected from:corticosteroids, anti-emetic agents, analgesics, anti-cancer agents,anti-inflammatories, kinase inhibitors, antibodies, HSP90 inhibitors,histone deacetylase (HDAC) inhibitors, and aromatase inhibitors.

Pharmaceutical formulations described herein are administered to amammal in a variety of ways, including but not limited to, oral,parenteral (e.g., intravenous, subcutaneous, intramuscular), buccal,topical or transdermal administration routes. The pharmaceuticalformulations described herein include, but are not limited to, aqueousliquid dispersions, self-emulsifying dispersions, solid solutions,liposomal dispersions, solid dosage forms, powders, immediate releaseformulations, controlled release formulations, fast melt formulations,tablets, capsules, pills, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate and controlled release formulations.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, areadministered orally.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, areadministered systemically.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), or (VI), are administered intravenously.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, areadministered subcutaneously.

In some embodiments, the compounds of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, areadministered topically. In such embodiments, the compound of Formula(I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptablesalt thereof, is formulated into a variety of topically administrablecompositions, such as solutions, suspensions, lotions, gels, pastes,shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages,balms, creams or ointments. In some embodiments, the compounds ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, are administered topically to the skin ofmammal.

In another aspect is the use of a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for treating a disease, disorder orconditions in which the activity of estrogen receptors contributes tothe pathology and/or symptoms of the disease or condition. In oneaspect, the disease or condition is any of the diseases or conditionsspecified herein.

In any of the aforementioned aspects are further embodiments in whichthe effective amount of the compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, is: (a)systemically administered to the mammal; and/or (b) administered orallyto the mammal; and/or (c) intravenously administered to the mammal;and/or (d) administered by injection to the mammal; and/or (e)administered topically to the mammal; and/or (f) adminsterednon-systemically or locally to the mammal.

In any of the aforementioned aspects are further embodiments comprisingsingle administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredonce; (ii) the compound is administered to the mammal multiple timesover the span of one day; (iii) continually; or (iv) continuously.

In any of the aforementioned aspects are further embodiments comprisingmultiple administrations of the effective amount of the compound,including further embodiments in which (i) the compound is administeredcontinuously or intermittently: as in a single dose; (ii) the timebetween multiple administrations is every 6 hours; (iii) the compound isadministered to the mammal every 8 hours; (iv) the compound isadministered to the mammal every 12 hours; (v) the compound isadministered to the mammal every 24 hours. In further or alternativeembodiments, the method comprises a drug holiday, wherein theadministration of the compound is temporarily suspended or the dose ofthe compound being administered is temporarily reduced; at the end ofthe drug holiday, dosing of the compound is resumed. In one embodiment,the length of the drug holiday varies from 2 days to 1 year.

Also provided is a method of reducing ER activation in a mammalcomprising administering to the mammal at least one compound having thestructure of F Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof. In some embodiments, themethod comprises reducing ER activation in breast cells, lung cells,ovarian cells, colon cells, prostate cells, endometrial cells, oruterine cells in the mammal. In some embodiments, the method comprisesreducing ER activation in breast cells, ovarian cells, colon cells,prostate cells, endometrial cells, or uterine cells in the mammal. Insome embodiments, the method of reducing ER activation in the mammalcomprises reducing the binding of estrogens to estrogen receptors in themammal. In some embodiments, the method of reducing ER activation in themammal comprises reducing ER concentrations in the mammal.

In one aspect is the use of a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, inthe treatment or prevention of diseases or conditions of the uterus in amammal. In some embodiments, the disease or condition of the uterus isleiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.In some embodiments, the disease or condition of the uterus is acancerous disease or condition of the uterus. In some other embodiments,the disease or condition of the uterus is a non-cancerous disease orcondition of the uterus.

In one aspect is the use of a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for the treatment of diseases orconditions that are estrogen sensitive, estrogen receptor dependent orestrogen receptor mediated. In some embodiments, the disease orcondition is breast cancer, lung cancer, ovarian cancer, colon cancer,prostate cancer, endometrial cancer, or uterine cancer. In someembodiments, the disease or condition is described herein.

In some cases disclosed herein is the use of a compound of Formula (I),(II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, in the treatment or prevention of diseases or conditions thatare estrogen sensitive, estrogen receptor dependent or estrogen receptormediated. In some embodiments, the disease or condition is describedherein.

In any of the embodiments disclosed herein, the mammal is a human.

In some embodiments, compounds provided herein are used to diminish,reduce, or eliminate the activity of estrogen receptors.

Articles of manufacture, which include: packaging material; a compoundof Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, or composition thereof, within the packagingmaterial; and a label that indicates that the compound orpharmaceutically acceptable salt, active metabolite, prodrug, orpharmaceutically acceptable solvate thereof, or composition thereof, orcomposition thereof, is used for reducing, diminishing or eliminatingthe effects of estrogen receptors, or for the treatment, prevention oramelioration of one or more symptoms of a disease or condition thatwould benefit from a reduction or elimination of estrogen receptoractivity, are provided.

Other objects, features and advantages of the compounds, methods andcompositions described herein will become apparent from the followingdetailed description. It should be understood, however, that thedetailed description and the specific examples, while indicatingspecific embodiments, are given by way of illustration only, sincevarious changes and modifications within the spirit and scope of theinstant disclosure will become apparent to those skilled in the art fromthis detailed description

DETAILED DESCRIPTION OF THE INVENTION

Estrogen receptor alpha (ER-α; NR3A1) and estrogen receptor beta (ER-β;NR3A2) are steroid hormone receptors, which are members of the largenuclear receptor superfamily. Nuclear receptors share a common modularstructure, which minimally includes a DNA binding domain (DBD) and aligand binding domain (LBD). Steroid hormone receptors are soluble,intracellular proteins that act as ligand-regulated transcriptionfactors. Vertebrates contain five closely related steroid hormonereceptors (estrogen receptor, androgen receptor, progesterone receptor,glucocorticoid receptor, mineralcorticoid receptor), which regulate awide spectrum of reproductive, metabolic and developmental activities.The activities of ER are controlled by the binding of endogenousestrogens, including 17β-estradiol and estrones.

The ER-α gene is located on 6q25.1 and encodes a 595 AA protein. TheER-β gene resides on chromosome 14q23.3 and produces a 530 AA protein.However, due to alternative splicing and translation start sites, eachof these genes can give rise to multiple isoforms. In addition to theDNA binding domain (called C domain) and ligand binding domain (Edomain) these receptors contain an N-terminal (A/B) domain, a hinge (D)domain that links the C and E domains, and a C-terminal extension (Fdomain) (Gronemeyer and Laudet; Protein Profile 2: 1173-1308, 1995).While the C and E domains of ER-α and ER-β are quite conserved (95% and55% amino acid identity, respectively), conservation of the A/B, D and Fdomains is poor (below 30% amino acid identity). Both receptors areinvolved in the regulation and development of the female reproductivetract but also play various roles in the central nervous system,cardiovascular systems and bone metabolism.

The ligand binding pocket of steroid hormone receptors is deeply buriedwithin the ligand binding domain. Upon binding, the ligand becomes partof the hydrophobic core of this domain. Consequently most steroidhormone receptors are instable in the absence of hormone and requireassistance from chaperones, such as Hsp90, in order to maintainhormone-binding competency. The interaction with Hsp90 also controlsnuclear translocation of these receptors. Ligand-binding stabilizes thereceptor and initiates sequential conformational changes that releasethe chaperones, alter the interactions between the various receptordomains and remodel protein interaction surfaces that allow thesereceptors to translocate into the nucleus, bind DNA and engage ininteractions with chromatin remodeling complexes and the transcriptionalmachinery. Although ER can interact with Hsp90, this interaction is notrequired for hormone binding and, dependent on the cellular context,apo-ER can be both cytoplasmic and nuclear. Biophysical studiesindicated that DNA binding rather than ligand binding contributes to thestability of the receptor (Greenfield et al., Biochemistry 40:6646-6652, 2001).

ER can interact with DNA either directly by binding to a specific DNAsequence motif called estrogen response element (ERE) (classicalpathway), or indirectly via protein-protein interactions (nonclassicalpathway) (Welboren et al., Endocrine-Related Cancer 16: 1073-1089,2009). In the nonclassical pathway, ER has been shown to tether to othertranscription factors including SP-1, AP-1 and NF-κB. These interactionsappear to play critical roles in the ability of ER to regulate cellproliferation and differentiation.

Both types of ER DNA interactions can result in gene activation orrepression dependent on the transcriptional coregulators that arerecruited by the respective ER-ERE complex (Klinge, Steroid 65: 227-251,2000). The recruitment of coregulators is primarily mediated by twoprotein interaction surfaces, the AF2 and AF1. AF2 is located in the ERE-domain and its conformation is directly regulated by the ligand(Brzozowski et al., Nature 389: 753-758, 1997). Full agonists appear topromote the recruitment of co-activators, whereas weak agonists andantagonists facilitate the binding of co-repressors. The regulation ofprotein with the AF1 is less well understood but can be controlled byserine phosphorylation (Ward and Weigel, Biofactors 35: 528-536, 2009).One of the involved phosphorylation sites (S118) appears to control thetranscriptional activity of ER in the presence of antagonists such astamoxifen, which plays an important role in the treatment of breastcancer. While full agonists appear to arrest ER in certain conformation,weak agonists tend to maintain ER in equilibrium between differentconformations, allowing cell-dependent differences in co-regulatorrepertoires to modulate the activity of ER in a cell-dependent manner(Tamrazi et al., Mol. Endocrinol. 17: 2593-2602, 2003). Interactions ofER with DNA are dynamic and include, but are not limited to, thedegradation of ER by the proteasome (Reid et al., Mol Cell 11: 695-707,2003). The degradation of ER with ligands provides an attractivetreatment strategy for disease or conditions that estrogen-sensitiveand/or resistant to available anti-hormonal treatments.

ER signaling is crucial for the development and maintenance of femalereproductive organs including breasts, ovulation and thickening of theendometrium. ER signaling also has a role in bone mass, lipidmetabolism, cancers, etc. About 70% of breast cancers express ER-α (ER-αpositive) and are dependent on estrogens for growth and survival. Othercancers also are thought to be dependent on ER-α signaling for growthand survival, such as for example ovarian and endometrial cancers. TheER-α antagonist tamoxifen has been used to treat early and advanced ER-αpositive breast cancer in both pre- and post-menopausal women.Fulvestrant (Faslodex™) a steroid-based ER antagonist is used to treatbreast cancer in women which has have progressed despite therapy withtamoxifen. Steroidal and non-steroidal aromatase inhibitors are alsoused to treat cancers in humans. In some embodiments, the steroidal andnon-steroidal aromatase inhibitors block the production of estrogen fromandrostenedione and testosterone in post-menopausal women, therebyblocking ER dependent growth in the cancers. In addition to theseanti-hormonal agents, progressive ER positive breast cancer is treatedin some cases with a variety of other chemotherapeutics, such as forexample, the anthracylines, platins, taxanes. In some cases, ER positivebreast cancers that harbor genetic amplication of the ERB-B/HER2tyrosine kinase receptor are treated with the monoclonal antibodytrastuzumab (Herceptin™) or the small molecule pan-ERB-B inhibitorlapatinib. Despite this battery of anti-hormonal, chemotherapeutic andsmall-molecule and antibody-based targeted therapies, many women withER-α positive breast develop progressive metastatic disease and are inneed of new therapies. Importantly, the majority of ER positive tumorsthat progress on existing anti-hormonal, as well as and other therapies,are thought to remain dependent on ER-α for growth and survival. Thus,there is a need for new ER-α targeting agents that have activity in thesetting of metastatic disease and acquired resistance. In one aspect,described herein are compounds that are selective estrogen receptormodulators (SERMs). In specific embodiments, the SERMs described hereinare selective estrogen receptor degraders (SERDs). In some embodiments,in cell-based assays the compounds described herein result in areduction in steady state ER-α levels (i.e. ER degradation) and areuseful in the treatment of estrogen sensitive diseases or conditionsand/or diseases or conditions that have developed resistant toanti-hormonal therapies.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agent agentsthat can modulate other critical pathways in breast cancer, includingbut not limited to those that target IGF1R, EGFR, erB-B2 and 3 thePI3K/AKT/mTOR axis, HSP90, PARP or histone deacetylases.

Given the central role of ER-α in breast cancer development andprogression, compounds disclosed herein are useful in the treatment ofbreast cancer, either alone or in combination with other agent used totreat breast cancer, including but not limited to aromatase inhibitors,anthracylines, platins, nitrogen mustard alkylating agents, taxanes.Illustrative agent used to treat breast cancer, include, but are notlimited to, paclitaxel, anastrozole, exemestane, cyclophosphamide,epirubicin, fulvestrant, letrozole, gemcitabine, trastuzumab,pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene,vinorelbine, capecitabine, ixabepilone, as well as others describedherein.

ER-related diseases or conditions include ER-α dysfunction is associatedwith cancer (bone cancer, breast cancer, lung cancer, colorectal cancer,endometrial cancer, prostate cancer, ovarian and uterine cancer),central nervous system (CNS) defects (alcoholism, migraine),cardiovascular system defects (aortic aneurysm, susceptibility tomyocardial infarction, aortic valve sclerosis, cardiovascular disease,coronary artery disease, hypertension), hematological system defects(deep vein thrombosis), immune and inflammation diseases (Graves'Disease, arthritis, multiple sclerosis, cirrhosis), susceptibility toinfection (hepatitis B, chronic liver disease), metabolic defects (bonedensity, cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis), neurological defects (Alzheimer's disease, Parkinson'sdisease, migraine, vertigo), psychiatric defects (anorexia nervosa,attention deficity hyperactivity disorder (ADHD), dementia, majordepressive disorder, psychosis) and reproductive defects (age ofmenarche, endometriosis, infertility.

In some embodiments, compounds disclosed herein are used in thetreatment of an estrogen receptor dependent or estrogen receptormediated disease or condition in mammal.

In some embodiments, the estrogen receptor dependent or estrogenreceptor mediated disease or condition is selected from cancer, centralnervous system (CNS) defects, cardiovascular system defects,hematological system defects, immune and inflammation diseases,susceptibility to infection, metabolic defects, neurological defects,psychiatric defects and reproductive defects.

In some embodiments, the estrogen receptor dependent or estrogenreceptor mediated disease or condition is selected from bone cancer,breast cancer, lung cancer, colorectal cancer, endometrial cancer,prostate cancer, ovarian cancer, uterine cancer, alcoholism, migraine,aortic aneurysm, susceptibility to myocardial infarction, aortic valvesclerosis, cardiovascular disease, coronary artery disease,hypertension, deep vein thrombosis, Graves' Disease, arthritis, multiplesclerosis, cirrhosis, hepatitis B, chronic liver disease, bone density,cholestasis, hypospadias, obesity, osteoarthritis, osteopenia,osteoporosis, Alzheimer's disease, Parkinson's disease, migraine,vertigo, anorexia nervosa, attention deficity hyperactivity disorder(ADHD), dementia, major depressive disorder, psychosis, age of menarche,endometriosis, and infertility.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal. In some embodiments, the cancer is breast cancer, ovariancancer, endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer, lung cancer, ovarian cancer,endometrial cancer, prostate cancer, or uterine cancer. In someembodiments, the cancer is breast cancer. In some embodiments, thecancer is a hormone dependent cancer. In some embodiments, the cancer isan estrogen receptor dependent cancer. In some embodiments, the canceris an estrogen-sensitive cancer. In some embodiments, the cancer isresistant to anti-hormonal treatment. In some embodiments, the cancer isan estrogen-sensitive cancer or an estrogen receptor dependent cancerthat is resistant to anti-hormonal treatment. In some embodiments, thecancer is a hormone-sensitive cancer or a hormone receptor dependentcancer that is resistant to anti-hormonal treatment. In someembodiments, anti-hormonal treatment includes treatment with at leastone agent selected from tamoxifen, fulvestrant, steroidal aromataseinhibitors, and non-steroidal aromatase inhibitors.

In some embodiments, compounds disclosed herein are used to treathormone receptor positive metastatic breast cancer in a postmenopausalwoman with disease progression following anti-estrogen therapy.

In some embodiments, compounds disclosed herein are used to treat ahormonal dependent benign or malignant disease of the breast orreproductive tract in a mammal. In some embodiments, the benign ormalignant disease is breast cancer.

In some embodiments, the compound used in any of the methods describedherein is an estrogen receptor degrader; is an estrogen receptorantagonist; has minimal or negligible estrogen receptor agonistactivity; or combinations thereof.

In some embodiments, methods of treatment with compounds describedherein include a treatment regimen that includes administering radiationtherapy to the mammal.

In some embodiments, methods of treatment with compounds describedherein include administering the compound prior to or following surgery.

In some embodiments, methods of treatment with compounds describedherein include administering to the mammal at least one additionalanti-cancer agent.

In some embodiments, compounds disclosed herein are used to treat cancerin a mammal, wherein the mammal is chemotherapy-naïve.

In some embodiments, compounds disclosed herein are used in thetreatment of cancer in a mammal. In some embodiments, compoundsdisclosed herein are used to treat cancer in a mammal, wherein themammal is being treated for cancer with at least one anti-cancer agent.In one embodiment, the cancer is a hormone refractory cancer.

In some embodiments, compounds disclosed herein are used in thetreatment or prevention of diseases or conditions of the uterus in amammal. In some embodiments, the disease or condition of the uterus isleiomyoma, uterine leiomyoma, endometrial hyperplasia, or endometriosis.In some embodiments, the disease or condition of the uterus is acancerous disease or condition of the uterus. In some other embodiments,the disease or condition of the uterus is a non-cancerous disease orcondition of the uterus.

In some embodiments, compounds disclosed herein are used in thetreatment of endometriosis in a mammal.

In some embodiments, compounds disclosed herein are used in thetreatment of leiomyoma in a mammal. In some embodiments, the leiomyomais a uterine leiomyoma, esophageal leiomyoma, cutaneous leiomyoma, orsmall bowel leiomyoma. In some embodiments, compounds disclosed hereinare used in the treatment of fibroids in a mammal. In some embodiments,compounds disclosed herein are used in the treatment of uterine fibroidsin a mammal.

Compounds

Compounds of Formula (I), (II), (III), (IV), (V), or (VI), includingpharmaceutically acceptable salts, prodrugs, active metabolites andpharmaceutically acceptable solvates thereof, are estrogen receptormodulators. In specific embodiments, the compounds described herein areestrogen receptor degraders. In specific embodiments, the compoundsdescribed herein are estrogen receptor antagonists. In specificembodiments, the compounds described herein are estrogen receptordegraders and estrogen receptor antagonists with minimal or no estrogenreceptor agonist activity.

In some embodiments, compounds disclosed herein are estrogen receptordegraders and estrogen receptor antagonists that exhibit: no estrogenreceptor agonism; and/or anti-proliferative activity against breastcancer, ovarian cancer, endometrial cancer, cervical cancer cell lines;and/or maximal anti-proliferative efficacy against breast cancer,ovarian cancer, endometrial cancer, cervical cell lines in-vitro; and/orminimal agonism in the human endometrial (Ishikawa) cell line; and/or noagonism in the human endometrial (Ishikawa) cell line; and/or no agonismin the immature rat uterine assay in-vivo; and/or inverse agonism in theimmature rat uterine assay in-vivo; and/or anti-tumor activity in breastcancer, ovarian cancer, endometrial cancer, cervical cancer cell linesin xenograft assays in-vivo or other rodent models of these cancers.

In some embodiments, compounds described herein have reduced or minimalinteraction with the hERG (the human Ether-à-go-go-Related Gene) channeland/or show a reduced potential for QT prolongation and/or a reducedrisk of ventricular tachyarrhythmias like torsades de pointes.

In some embodiments, compounds described herein have reduced or minimalpotential to access the hypothalamus and/or have reduced or minimalpotential to modulate the Hypothalamic-Pituitary-Ovarian (HPO) axisand/or show a reduced potential to cause hyper-stimulation of theovaries and/or show a reduced potential for ovary toxicity.

In some embodiments, compounds described herein for use in the treatmentof a disease or condition in a pre-menopausal woman have reduced orminimal potential to access the hypothalamus and/or have reduced orminimal potential to modulate the Hypothalamic-Pituitary-Ovarian (HPO)axis and/or show a reduced potential to cause hyper-stimulation of theovaries and/or show a reduced potential for ovary toxicity. In someembodiments, the disease or condition in the pre-menopausal woman isendometriosis. In some embodiments, the disease or condition in thepre-menopausal woman is an uterine disease or condition.

In one aspect, described herein is a compound of Formula (I), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₁₀ heterocycloalkyl;        -   each R²³ is independently F or C₁-C₆-fluoroalkyl;        -   t is 1, 2, 3, or 4;    -   R⁴ is H, halogen, —CN, C₁-C₄alkyl, C₁-C₄-fluoroalkyl or        C₃-C₆cycloalkyl;    -   R⁵ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,        C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   each R⁶ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   R⁷ is H or C₁-C₄alkyl;    -   each R⁸ is independently selected from H, halogen, —CN, —OH,        C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, and        C₁-C₆alkoxy;    -   each R¹⁰ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R¹¹ is independently selected from H, —C(═O)R¹²,        —C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl,        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹² is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2;    -   provided that the compound is not        2-(4-((S)-2-(R)-3-fluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol.

For any and all of the embodiments described herein, substituents areselected from among a subset of the listed alternatives. For example insome embodiments, R⁷ is H or —CH₃. In other embodiments, R⁷ is H.

In some embodiments,

is a monocyclic C₂-C₁₀ heterocycloalkyl; each R²³ is independentlyC₁-C₆-fluoroalkyl; t is 1, 2, 3, or 4.

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form

is a monocyclic C₂-C₁₀ heterocycloalkyl

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form

is a monocyclic C₂-C₆ heterocycloalkyl.

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form

is a 4-, 5-, 6- or 7-membered monocyclic C₂-C₆heterocycloalkyl. In someembodiments,

is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl. In some otherembodiments,

is pyrrolidinyl.

In some embodiments, R¹ is H or C₁-C₆alkyl; R² is H, C₁-C₆alkyl, orC₁-C₆-fluoroalkyl; R³ is C₁-C₆-fluoroalkyl; or R² and R³ are takentogether with the N atom to which they are attached to form

is a 4-, 5-, 6- or 7-membered monocyclic C₂-C₆heterocycloalkyl; each R²³is independently F or C₁-C₆-fluoroalkyl; t is 1 or 2; R⁴ is —CH₃; R⁷ isH; p is 0 or 1.

In some embodiments, R¹ is H or C₁-C₆alkyl; R² is H, C₁-C₆alkyl, orC₁-C₆-fluoroalkyl; R³ is C₁-C₆-fluoroalkyl; or R² and R³ are takentogether with the N atom to which they are attached to form

is a 4-, 5-, 6- or 7-membered monocyclic C₂-C₆heterocycloalkyl; each R²³is independently C₁-C₆-fluoroalkyl; t is 1 or 2; R⁴ is —CH₃; R⁷ is H; pis 0 or 1.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, each R¹⁰ is independently selected from —CN, —OH,—OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl. In someembodiments, each R¹⁰ is independently selected from H, halogen, —CN,—OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl. In someembodiments, each R¹⁰ is independently selected from H, F, Cl, —CN,—CH₃, and —CF₃. In some embodiments, each R¹⁰ is independently selectedfrom H and F.

In some embodiments, n is 0 or 1. In some embodiments, n is 0.

In some embodiments, R⁵ is —OR¹¹. In some embodiments, R¹¹ is H. In someembodiments, R⁵ is —OH; R¹¹ is H.

In some embodiments, R⁵ is —OH; each R¹⁰ is independently selected fromH, halogen, —CN, —OH, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R¹¹ is H.

In some embodiments, each R⁶ is independently selected from H, halogen,—CN, —OH, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, andC₁-C₆alkoxy. In some embodiments, each R⁶ is independently selected fromH, halogen, and —CN. In some embodiments, each R⁶ is H, F, Cl, —CN,—CH₃, and —CF₃. In some embodiments, m is 0 or 1. In some embodiments, mis 0.

In some embodiments, R⁴ is —CH₃.

In some embodiments, R¹ is H or —CH₃. In some embodiments, R¹ is —CH₃.

In some embodiments, R¹ is H, or —CH₃; R² and R³ are taken together withthe N atom to which they are attached to form

is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, orpiperazinyl; each R²³ is independently F, —CH₂F, —CHF₂, —CF₃, —CHFCH₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃,—CH(CF₃)₂, or —CF(CH₃)₂.

In some embodiments, R¹ is H, or —CH₃; R² and R³ are taken together withthe N atom to which they are attached to form

is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, orpiperazinyl; each R²³ is independently —CH₂F, —CHF₂, —CF₃, —CHFCH₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃,—CH(CF₃)₂, or —CF(CH₃)₂.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound has one of the following structures:

-   -   or is a pharmaceutically acceptable salt, or solvate thereof.

In some embodiments, the compound of Formula (I) has the structure ofFormula (II):

-   -   or is a pharmaceutically acceptable salt, or solvate thereof

In some embodiments of the compound of Formula (II), R¹ is H or —CH₃; isa monocyclic C₂-C₆heterocycloalkyl; each R²³ is independentlyC₁-C₆-fluoroalkyl; t is 1 or 2; R⁵ is —OR¹¹; each R⁶ is independentlyselected from H, halogen, —CN, —OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹²,C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; each R¹⁰ is independently selected from H, halogen,—CN, —OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; each R¹¹ is independently selected from H, —C(═O)R¹²,—C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl,C₁-C₆-fluoroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted aryl), and—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); each R¹² isindependently selected from substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl, substituted orunsubstituted C₁-C₆-fluoroalkyl, substituted or unsubstitutedC₃-C₁₀cycloalkyl, substituted or unsubstituted C₂-C₁₀heterocycloalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —C₁-C₂alkylene-(substituted or unsubstitutedC₃-C₁₀cycloalkyl), —C₁-C₂alkylene-(substituted or unsubstitutedC₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or unsubstitutedaryl), and —C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); mis 0 or 1; n is 0 or 1. In some embodiments, m is 0. In someembodiments, n is 0. In some embodiments, each R¹¹ is H.

In some other embodiments of the compound of Formula (II), R¹ is H or—CH₃;

R²³ is C₁-C₄-fluoroalkyl; R⁵ is —OR¹¹; each R⁶ is independently selectedfrom H, halogen, and —CN; each R¹⁰ is independently selected from H,halogen and —CN; each R¹¹ is independently selected from H, —C(═O)R¹²,—C(═O)OR¹², —C(═O)NHR¹², and C₁-C₆alkyl; each R¹² is independentlyselected from substituted or unsubstituted C₁-C₆alkyl, substituted orunsubstituted C₁-C₆heteroalkyl, substituted or unsubstitutedC₁-C₆-fluoroalkyl, substituted or unsubstituted C₃-C₁₀cycloalkyl,substituted or unsubstituted C₂-C₁₀heterocycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl,—C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted C₂-C₁₀heterocycloalkyl),—C₁-C₂alkylene-(substituted or unsubstituted aryl), and—C₁-C₂alkylene-(substituted or unsubstituted heteroaryl); m is 0 or 1; nis 0 or 1. In some embodiments, each R¹¹ is H. In some embodiments, m is0. In some embodiments, n is 0.

In some embodiments,

In some embodiments,

In another aspect, described herein is a compound of Formula (III), or apharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   R¹ is C₁-C₆-fluoroalkyl;

-   -    is a monocyclic C₂-C₁₀heterocycloalkyl;        -   each R²³ is independently F, C₁-C₆alkyl or            C₁-C₆-fluoroalkyl;        -   t is 0, 1, 2, 3, or 4;    -   R⁴ is H, halogen, —CN, C₁-C₄alkyl, C₁-C₄-fluoroalkyl or        C₃-C₆cycloalkyl;    -   R⁵ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,        C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl;    -   each R⁶ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R⁸ is independently selected from H, halogen, —CN, —OH,        C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, and        C₁-C₆alkoxy;    -   each R¹⁰ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,        C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and        C₁-C₆heteroalkyl;    -   each R¹¹ is independently selected from H, —C(═O)R¹²,        —C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl,        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹² is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2.

In some embodiments, R¹ is —CH₂F, —CHF₂, or —CF₃;

is an azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl; each R²³ isindependently F, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or—CF(CH₃)₂; t is 0, 1 or 2; R⁴ is —CH₃; R⁷ is H; p is 0 or 1.

In some embodiments, the compound of Formula (I), (II) or (III) has oneof the following structures:

In some embodiments, the compound of Formula (I), (II) or (III) has thefollowing structure:

In some embodiments, the compound of Formula (I), (II) or (III) has thefollowing structure:

In some embodiments, R⁵ is —OH; each R¹⁰ is independently selected fromH, halogen, —CN, —OH, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R¹¹ is H. In some embodiments, R⁵ is —OH; each R⁶ isindependently selected from H and halogen; each R¹⁰ is independentlyselected from H and halogen; R¹¹ is H.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, each R²³ is independently F, —CH₃, —CH₂CH₃, —CH₂F,—CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂. In some embodiments,each R²³ is independently F, —CH₃, —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently F, —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently —CH₂F, —CHF₂, or —CF₃. In someembodiments, each R²³ is independently —CH₂F. In some embodiments, eachR²³ is independently —CH₃, —CH₂F, —CHF₂, or —CF₃. In some embodiments,each R²³ is independently —CH₃.

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form substituted or unsubstitutedpyrrolidinyl.

In some embodiments, R¹ is —CH₃. In some embodiments, R¹ is —CH₃; R⁴ is—CH₃.

In some embodiments, described herein is a compound of Formula (IV), ora pharmaceutically acceptable salt, or solvate thereof:

wherein,

-   -   L is a substituted or unsubstituted C₁-C₆fluoroalkylene, where        if L is substituted, then L is substituted with 1 or 2 R¹;    -   R¹ is C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₃-C₆cycloalkyl,        C₃-C₆-fluorocycloalkyl, or C₁-C₆heteroalkyl;    -   R² is H or R¹²;    -   R³ is —C(═O)R¹², —C(═O)OR¹², —C(═O)NHR¹², —S(═O)₂R¹², or R¹²;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic heterocycloalkyl or a bicyclic        heterocycloalkyl;        -   each R²³ is independently selected from F, Cl, —CN, —OH,            —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹², substituted            or unsubstituted C₁-C₆alkyl, substituted or unsubstituted            C₁-C₆-fluoroalkyl, substituted or unsubstituted            C₁-C₆-fluoroalkoxy, substituted or unsubstituted            C₁-C₆alkoxy, and substituted or unsubstituted            C₁-C₆heteroalkyl;        -   or two R²³ on the same carbon atom are taken together with            the carbon atom to which they are attached to form —C(═O)—;        -   or two R²³ on adject carbon atoms are taken together with            the carbon atoms to which they are attached to form a            C₃-C₆cycloalkyl;        -   or 1 R²³ is taken together with R¹ and the intervening atoms            connecting R²³ to R¹ to form a 5-7 membered ring;        -   t is 0, 1, 2, 3, or 4;    -   R⁴ is H, halogen, —CN, C₁-C₄alkyl, C₁-C₄-fluoroalkyl,        C₁-C₄alkoxy, C₁-C₄-fluoroalkoxy, C₃-C₆cycloalkyl,        C₃-C₆-fluorocycloalkyl, C₃-C₆heterocycloalkyl, C₁-C₆heteroalkyl,        —C₁-C₄alkylene-C₃-C₆cycloalkyl, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹²,        —C(═O)R¹², —C(═O)NHR¹², or —C(═O)N(R¹²)₂;    -   R⁵ is H, halogen, —CN, —NHR¹¹, —NR¹¹R¹², —SR¹¹, —S(═O)R¹²,        —S(═O)₂R¹², —C(═O)R¹², —C(═O)OH, —C(═O)OR¹², —C(═O)NHR¹²,        —C(═O)N(R¹²)₂, substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆-fluoroalkyl, substituted or        unsubstituted C₁-C₆-fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₁-C₆-fluoroalkyl, or a substituted        or unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   each R⁶ is independently selected from H, halogen, —CN, —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹², —C(═O)OH, —C(═O)OR¹²,        —C(═O)NHR¹², —C(═O)N(R¹²)₂, substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆-fluoroalkyl,        substituted or unsubstituted C₁-C₆-fluoroalkoxy, substituted or        unsubstituted C₁-C₆alkoxy, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl;    -   R⁷ is H or C₁-C₄alkyl;    -   each R⁸ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy,        and substituted or unsubstituted C₁-C₆heteroalkyl;    -   R⁹ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,        —S(═O)R¹², —S(═O)₂R¹², substituted or unsubstituted C₁-C₆alkyl,        substituted or unsubstituted C₁-C₆-fluoroalkyl, substituted or        unsubstituted C₁-C₆-fluoroalkoxy, substituted or unsubstituted        C₁-C₆alkoxy, and substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted or        unsubstituted C₂-C₁₀heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   each R¹⁹ is independently selected from H, halogen, —CN, —OH,        —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkoxy, substituted or unsubstituted C₁-C₆alkoxy,        and substituted or unsubstituted C₁-C₆heteroalkyl;    -   each R¹¹ is independently selected from H, —C(═O)R¹²,        —C(═O)OR¹², —C(═O)NHR¹², substituted or unsubstituted        C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,        substituted or unsubstituted C₁-C₆-fluoroalkyl, substituted or        unsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   each R¹² is independently selected from substituted or        unsubstituted C₁-C₆alkyl, substituted or unsubstituted        C₁-C₆heteroalkyl, substituted or unsubstituted        C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₁₀cycloalkyl, substituted or unsubstituted        C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl,        —C₁-C₂alkylene-(substituted or unsubstituted C₃-C₁₀cycloalkyl),        —C₁-C₂alkylene-(substituted or unsubstituted        C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted or        unsubstituted aryl), and —C₁-C₂alkylene-(substituted or        unsubstituted heteroaryl);    -   Y is —O—, —S—, —S(═O)—, —S(═O)₂—, or —NR¹³—; R¹³ is H,        —C(═O)R¹², substituted or unsubstituted C₁-C₆alkyl, substituted        or unsubstituted C₁-C₆-fluoroalkyl, substituted or unsubstituted        C₃-C₇cycloalkyl, or substituted or unsubstituted        C₁-C₆heteroalkyl;    -   X is —O—, —S—, —S(═O)—, —S(═O)₂—, —CH₂—, —NH— or        —N(C₁-C₆alkyl)-;    -   m is 0, 1, 2, 3 or 4;    -   n is 0, 1, or 2;    -   p is 0, 1, or 2.

In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0 or 1.In some embodiments, p is 1. In some embodiments, p is 0.

In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1.In some embodiments, n is 0. In some embodiments, n is 1. In someembodiments, n is 1 or 2.

In some embodiments, m is 0, 1, 2, 3 or 4. In some embodiments, m is 1,2, 3 or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments,m is 0, 1, or 2. In some embodiments, m is 0, or 1. In some embodiments,m is 1, 2, or 3. In some embodiments, m is 1, or 2. In some embodiments,m is 1. In some embodiments, m is 0 or 1. In some embodiments, m is 0.

In some embodiments, Y is —O—. In some embodiments, X is —O—.

In some embodiments, L is a substituted or unsubstituted fluoroethylene,where if L is substituted, then L is substituted with 1 or 2 R¹; R⁴ isC₁-C₄alkyl; R⁵ is halogen, —CN, —NHR¹¹, —NR¹¹R¹², —SR¹¹, —S(═O)R¹²,—S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy,C₁-C₆alkoxy, C₁-C₆heteroalkyl, substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl,substituted or unsubstituted phenyl, or substituted or unsubstitutedmonocyclic heteroaryl; each R⁶ is independently selected from H,halogen, —CN, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹², —C(═O)OH,—C(═O)OR¹², —C(═O)NHR¹², —C(═O)N(R¹²)₂, C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl; R⁷is H; R⁹ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹,—S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹², —C(═O)OH, —C(═O)OR¹², —C(═O)NHR¹²,—C(═O)N(R¹²)₂, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy,C₁-C₆heteroalkyl, C₁-C₆-fluoroalkyl, or a substituted or unsubstitutedC₃-C₆cycloalkyl, substituted or unsubstituted C₂-C₆heterocycloalkyl,substituted or unsubstituted phenyl, or substituted or unsubstitutedmonocyclic heteroaryl; each R⁸ is independently selected from H,halogen, —CN, —OH, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy,and C₁-C₆alkoxy; each R¹⁰ is independently selected from H, halogen,—CN, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl; Y is —O—; X is—O—; p is 0 or 1.

In some embodiments, R⁵ is —OH or —OR¹¹; R⁹ is —OH or —OR¹¹; p is 0 or1.

In some embodiments, the compound of Formula (IV) has the followingstructure:

In some embodiments, R² is H, substituted or unsubstituted C₁-C₆alkyl,substituted or unsubstituted C₁-C₆heteroalkyl, or substituted orunsubstituted C₁-C₆-fluoroalkyl; R³ is —C(═O)R¹², —C(═O)OR¹²,—C(═O)NHR¹², —S(═O)₂R¹², or R¹²; R⁴ is C₁-C₄alkyl; R⁷ is H; Y is —O—; Xis —O—.

In some embodiments, R⁴ is C₁-C₄alkyl. In some embodiments, R⁴ isC₁-C₄-fluoroalkyl. In some embodiments, R⁴ is H, halogen, —CN,C₁-C₄-fluoroalkyl, C₁-C₄alkoxy, C₁-C₄-fluoroalkoxy, C₃-C₆cycloalkyl,C₃-C₆-fluorocycloalkyl, C₃-C₆heterocycloalkyl, C₁-C₆heteroalkyl,—C₁-C₄alkylene-C₃—SR¹¹, —S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹², C₆cycloalkyl,—C(═O)NHR¹², or —C(═O)N(R¹²)₂. In some embodiments, R⁴ is halogen, —CN,C₁-C₄alkoxy, C₁-C₄-fluoroalkoxy, C₃-C₆cycloalkyl,C₃-C₆-fluorocycloalkyl, C₃-C₆heterocycloalkyl, C₁-C₆heteroalkyl,—C₁-C₄alkylene-C₃-C₆cycloalkyl, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², —C(═O)R¹²,—C(═O)NHR¹², or —C(═O)N(R¹²)₂.

In some embodiments, R⁹ is —OH or —OR¹¹. In some embodiments, R⁹ is —OH.In some embodiments, R⁹ is —OH or —OR¹¹; p is 0 or 1.

In some embodiments, R⁵ is —OH. In some embodiments, R⁵ is —OH or —OR¹¹;p is 0 or 1.

In some embodiments, R⁹ is —OR¹¹. In some embodiments, R⁹ is —OH. Insome embodiments, R⁵ is —OR¹¹. In some embodiments, R⁵ is —OH. In someembodiments, R⁹ is —OR¹¹; and R⁵ is —OR¹¹. In some embodiments, R¹¹ isH. In some embodiments, R⁹ is —OH; and R⁵ is —OH.

In some embodiments, R⁴ is C₁-C₄alkyl; each R⁶ is independently selectedfrom H, halogen, —CN, —OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹²,C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R⁷ is H; each R⁸ is independently selected from H,halogen, —CN, —OH, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy,and C₁-C₆alkoxy; Y is —O—; X is —O—; p is 0 or 1.

In some embodiments, R⁹ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹,—NR¹¹R¹², —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl; each R¹⁰ isindependently selected from H, halogen, —CN, —OH, —OR¹¹, —SR¹¹,—S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments, R⁴ is C₁-C₄alkyl; R⁵ is H, halogen, —CN, —OH,—OR¹¹, —NHR¹¹, —NR¹¹R¹², —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl,C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl;each R⁶ is independently selected from H, halogen, —CN, —OH, —OR¹¹,—SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl; R⁷ is H; Y is—O—; X is —O—.

In some embodiments, R⁴ is C₁-C₄alkyl; each R⁶ is independently selectedfrom H, halogen, —CN, —OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹²,C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; R⁷ is H; each R⁸ is independently selected from H,halogen, —CN, —OH, C₁-C₆alkyl, C₁-C₆-fluoroalkyl, C₁-C₆-fluoroalkoxy,and C₁-C₆alkoxy; Y is —O—; X is —O—; p is 0 or 1.

In some embodiments, R⁹ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹,—NR¹¹R¹², —SR¹¹, —S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, C₁-C₆heteroalkyl, substituted orunsubstituted C₃-C₆cycloalkyl, substituted or unsubstitutedC₂-C₆heterocycloalkyl, substituted or unsubstituted phenyl, orsubstituted or unsubstituted monocyclic heteroaryl; each R¹⁰ isindependently selected from H, halogen, —CN, —OH, —OR¹¹, —SR¹¹,—S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆-fluoroalkyl,C₁-C₆-fluoroalkoxy, C₁-C₆alkoxy, and C₁-C₆heteroalkyl.

In some embodiments,

is azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl,piperazinyl, 3-azabicyclo[3.1.0]hexan-3-yl,3-azabicyclo[3.2.0]heptan-3-yl, or octahydrocyclopenta[c]pyrrolyl. Insome embodiments,

is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl. In someembodiments,

is pyrrolidinyl.

In some embodiments,

In some embodiments, each R²³ is independently selected from F, Cl, —CN,—OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F,—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂,—CF(CH₃)₂, —OCF₃, —OCH₂CF₃, —OCH₃, —OCH₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, and—CH₂OH. In some embodiments, each R²³ is independently selected from F,Cl, —CN, —OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CH₂F, —CHF₂, —CF₃, —CHFCH₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃,—CH(CF₃)₂, —CF(CH₃)₂, —OCF₃, —OCH₂CF₃, —OCH₃, —OCH₂CH₃, —CH₂OCH₃,—CH₂OCH₂CH₃, and —CH₂OH, provided that at least one R²³ is a F or afluoroalkyl.

In some embodiments, each R²³ is independently selected from F, Cl, —CN,—OH, —CH₃, —CH₂CH₃, —CH(CH₃)₂, —CF₃, —CH₂CF₃, —OCF₃, —OCH₂CF₃, —OCH₃,—OCH₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, and —CH₂OH.

In some embodiments, each R²³ is independently selected from F, —CH₃,—CH₂CH₃, —CH₂F, —CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃,—CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂. In someembodiments, each R²³ is independently selected from —CH₃, —CH₂CH₃,—CH₂F, —CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂.

In some embodiments, each R²³ is independently selected from F, —CH₂F,—CHF₂, —CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃,—CH₂CH₂CH₂CF₃, —CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂. In some embodiments,each R²³ is independently selected from —CH₂F, —CHF₂, —CF₃, —CHFCH₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CHCH₃CF₃,—CH(CF₃)₂, or —CF(CH₃)₂. In some embodiments, each R²³ is independentlyselected from —CH₂F.

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments,

In some embodiments, R²³ is —CH₃. In some embodiments, R²³ is —CH₂F.

In some embodiments, R² and R³ are taken together with the N atom towhich they are attached to form substituted or unsubstitutedpyrrolidinyl.

In some embodiments, R¹ is H or —CH₃; R⁴ is —CH₃. In some embodiments,R¹ is —CH₃; R⁴ is —CH₃.

Compounds of Formula (I), (II), (III), or (IV), include, but are notlimited to, compounds in the following table.

TABLE 1 Structure Name

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-3-phenyl- 2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-3-phenyl- 2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-3-phenyl- 2H-chromen-6-ol

2-(4-(2-(3-fluoroazetidin-l-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-(4-fluoropiperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-(2-(4-(fluoromethyl)piperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-(4-(fluoromethyl)piperidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-(3-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((R)-3-(difluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(difluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-(3-(trifluoromethyl)azetidin-1-yl)ethoxy) phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-((R)-(3-(trifluoromethyl)pyrrolidin-1-yl)ethoxy) phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((R)-3-(trifluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol

2-(4-(2-((S)-2-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-(2-((R)-3-fluoropiperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-6-ol

2-(4-(2-((S)-2-(difluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-(2-((S)-2-(difluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-((S)-2-((S)-2-(difluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-fluoropiperidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- (2-((S)-(trifluoromethyl)azetidin-1-yl)ethoxy)phenyl)-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)piperidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromcn-6-ol

2-(4-(2-(3-(2-fluoroethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((S)-3-(2-fluoroethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((S)-3-(2-fluoroethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((S)-3-(2-fluoroethyl)piperidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-(3-(2,2,2-trifluoroethyl)azetidin-1-yl) ethoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-((S)-3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((S)-2-((S)-3-(2,2,2-trifluoroethyl)pyrrolidin-1-yl)propoxy)phenyl)- 2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2- (4-((S)-2-((S)-3-(2,2,2-trifluoroethyl)piperidin-1-yl)propoxy)phenyl)- 2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-(3-(3,3,3-trifluoropropyl)azetidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-(2-((R)-3-(3,3,3-trifluoropropyl)pyrrolidin-1-yl)ethoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((S)-2-((R)-3-(3,3,3-trifluoropropyl)pyrrolidin-1-yl)propoxy)phenyl)- 2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((S)-2-((S)-3-(3,3,3-trifluoropropyl)piperidin-1-yl)propoxy)phenyl)-2H- chromen-6-ol

2-(4-((R)-3-fluoro-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-3-(3- hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(4-((R)-3-fluoro-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(4-((R)-3-fluoro-2-((R)-3-fluoropiperidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((R)-3,3-difluoro-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-3-(3- hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(4-((R)-3,3-difluoro-2-((R)-3- (fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((R)-3,3,3-trifluoro-2-((R)-3-(fluoromethyl)pyrrolidin-1- yl)propoxy)phenyl)-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((R)-3,3,3-trifluoro-2-((R)-3-methylpyrrolidin-1-yl)propoxy) phenyl)-2H-chromen-6-ol

2-(4-(2-((R)-3-fluoroazepan-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromethyl)azepan-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-chromen-6-ol

2-(4-(2-((R)-4-fluoroazepan-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-((S)-2-((R)-3-fluoroazepan-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)azepan-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((R)-3,3-difluoro-2-((R)-3- methylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-6-ol

2-(4-((R)-3-fluoro-2-((R)-3- methylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-6-ol

2-(4-((R)-3-fluoro-2-((R)-2- methylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-((R)-3,3-difluoro-2-((R)-2- methylpyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4- ((R)-3,3,3-trifluoro-2-((R)-2-methylpyrrolidin-1-yl)propoxy)phenyl)- 2H-chromen-6-ol

2-(4-((S)-2-((R)-4-fluoroazepan-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-4-(fluoromethyl)azepan-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((3R,4R)-3,4-bis(fluoromethyl) pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-6-ol

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromcthyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) propoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2-chloro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2-chloro-4-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2-chloro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen- 7-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-7-ol

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(4-hydroxyphenyl)- 4-methyl-2H-chromen-7-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy) phenyl)-4-methyl-2H-chromen-7-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) ethoxy)phenyl)-4-methyl-2H-chromen-7-ol

3-(3-fluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(2-fluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-7-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(3-chloro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-7-ol

3-(2-fluoro-5-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2-fluoro-5-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2-fluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-fluoro-5-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen- 6-ol

3-(3-fluoro-5-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-fluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4- (2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4- (2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2,4-difluoro-5-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2,4-difluoro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2,4-difluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3,4-difluoro-5-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(3,4-difluoro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin- 1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(3,4-difluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(4-fluorophenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(4-fluorophenyl)-4- methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(4-fluorophenyl)- 4-methyl-2H-chromen-6-ol

3-(4-chlorophenyl)-2-(4-(2-(3- (fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(4-chlorophenyl)-2-(4-(2-((R)-3- (fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(4-chlorophenyl)-2-(4-((S)-2- ((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(3-chlorophenyl)-2-(4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(3-chlorophenyl)-2-(4-(2-((R)-3- (fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(3-chlorophenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy) phenyl)-4-methyl-2H-chromen-6-ol

3-(3-chloro-4-fluorophenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy) phenyl)-4-methyl-2H-chromen-6-ol

3-(3-chloro-4-fluorophenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(3-chloro-4-fluorophenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl) propoxy)phenyl)-4-methyl-2H-chromen-6-ol

2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-fluorophenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-fluorophenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-fluorophenyl)- 4-methyl-2H-chromen-6-ol

3-(3,4-difluorophenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-2H-chromen-6-ol

3-(3,4-difluorophenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy) phenyl)-4-methyl-2H-chromen-6-ol

3-(3,4-difluorophenyl)-2-(4-((S)-2- ((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

3-(2,4-difluorophenyl)-2-(4-(2-(3- (fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

3-(2,4-difluorophenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy) phenyl)-4-methyl-2H-chromen-6-ol

3-(2,4-difluorophenyl)-2-(4-((S)-2- ((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H- chromen-6-ol

4-(2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-6-hydroxy-4-methyl- 2H-chromen-3-yl)benzonitrile

4-(2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-6-hydroxy-4-methyl- 2H-chromen-3-yl)benzonitrile

4-(2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-6-hydroxy-4-methyl-2H-chromen-3-yl)benzonitrile

2-(4-(2-(3-(fluoromethyl)azetidin-1- yl)ethoxy)phenyl)-4-methyl-3-(4-(methylsulfonyl)phenyl)-2H-chromen-6-ol

2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-3-(4- (methylsulfonyl)phenyl)-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-3-(4-(methylsulfonyl)phenyl)-2H-chromen-6-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(4-chloro-3-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(3-chloro-5-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(3-chloro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(3-chloro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(2-chloro-5-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(2-chloro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(2-chloro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

2-(2-(4-(2-(3-(fluoromethyl)azetidin-l-yl)ethoxy)phenyl)-6-hydroxy-4-methyl-2H-chromen-3-yl)-4-hydroxybenzonitrile

3-(2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-6-hydroxy-4-methyl-2H-chromen-3-yl)-5-hydroxybenzonitrile

4-(2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-6-hydroxy-4-methyl-2H-chromen-3-yl)-2-hydroxybenzonitrile

3-(3,5-difluoro-4-hydroxyphenyl)-2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(3,5-difluoro-4-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(3,5-difluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

2-(2-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(3-fluoro-4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(2-fluoro-4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(3-fluoro-4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(2-fluoro-4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(3-fluoro-4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

2-(4-(2-((3-fluoropropyl)(methyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-(2-(ethyl(3-fluoropropyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-(2-(ethyl(2-fluoroethyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-(2-(bis(2-fluoroethyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl- 2H-chromen-6-ol

2-(4-(2-(ethyl(3,3,3-trifluoropropyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4- methyl-2H-chromen-6-ol

2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-((S)-2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)propoxy) phenyl)-2H-chromen-6-ol

2-(4-((S)-2-((S)-2-(difluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-((S)-2-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

3-(3-hydroxyphenyl)-4-methyl-2-(4-((R)-3,3,3-trifluoro-2-(pyrrolidin-1-yl)propoxy) phenyl)-2H-chromen-6-ol

2-(4-((R)-3,3-difluoro-2-(pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4- 2H-chromen-6-ol

2-(4-((R)-3-fluoro-2-(pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((2S)-2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)propoxy)phenyl)-3- (3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

(3S,4S)-4-fluoro-1-((2S)-1-(4-(6-hydroxy-3-(3-hydroxyphenyl)-4-methyl-2H- chromen-2-yl)phenoxy)propan-2-yl)pyrrolidin-3-ol

2-(4-((S)-2-(3,3-difluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((S)-2-fluoro-2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(2,2-difluoro-2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(1-fluoro-2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-(1,1-difluoro-2-((R)-3-methylpyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-(4-((2S)-2-(2-fluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-2H-chromen-6-ol

2-(4-((S)-2-(2,2-difluoropyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)- 4-methyl-2H-chromen-6-ol

2-chloro-5-(4-cyclopropyl-2-(4-((S)-2-fluoro-2-morpholinoethoxy)phenyl)-6-hydroxy-2H-chromen-3-yl)benzonitrile

3-(4-chloro-3-hydroxyphenyl)-4-cyclopropyl-5-fluoro-2-(4-((S)-2-(4-fluoropiperidin-1-yl)propoxy)phenyl)-2H-chromen-6-ol

3-(4-chloro-3-hydroxyphenyl)-4-cyclopropyl-2-(4-((S)-2-(4,4-difluoropiperidin-1-yl)propoxy)phenyl)-7-fluoro-2H-chromen-6-ol

3-(4-fluoro-3-hydroxyphenyl)-2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(3-fluoro-5-hydroxyphenyl)-2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(2-fluoro-5-hydroxyphenyl)-2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)- 4-methyl-2H-chromen-6-ol

3-(2,4-difluoro-5-hydroxyphenyl)-2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

3-(3,4-difluoro-5-hydroxyphenyl)-2-(4-((S)-2-(3-(fluoromethyl)azetidin-1-yl)propoxy)phenyl)-4- methyl-2H-chromen-6-ol

In some embodiments, any one of the 2H-chromene compounds describedherein exists as a racemic mixture with respect to the stereochemistryat the 2-position of the 2H-chromene compound. In other embodiments anyone of the 2H-chromene compounds described herein exists as a singlestereoisomer with respect to the stereochemistry at the 2-position ofthe 2H-chromene compound. In some embodiments, any one of the2H-chromene compounds described herein exists as a (S)-isomer withrespect to the stereochemistry at the 2-position of the 2H-chromenecompound. In some other embodiments, any one of the 2H-chromenecompounds described herein exists as a (R)-isomer with respect to thestereochemistry at the 2-position of the 2H-chromene compound.

In some embodiments, a pharmaceutically acceptable salt of a compound ofFormula (I), (II), (III), or (IV) includes a pharmaceutically acceptablesalt of any one of the compound in the preceding table of compounds.

In another aspect, described herein is a compound with the structure ofFormula (V), or a pharmaceutically acceptable salt thereof:

wherein

-   -   SEMF is a selective estrogen receptor modulator fragment;    -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₆heterocycloalkyl;    -   each R²³ is independently C₁-C₆-fluoroalkyl, or F;    -   t is 1, 2, 3, or 4;    -   X is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —CH₂—, —NH—        or —N(C₁-C₆alkyl)-.

In another aspect, described herein is a compound with the followingstructure of Formula (VI), or a pharmaceutically acceptable saltthereof:

wherein,

-   -   SEMF is a selective estrogen receptor modulator fragment;    -   R¹ is C₁-C₆-fluoroalkyl;

-   -    is a monocyclic C₂-C₁₀heterocycloalkyl;    -   each R²³ is independently F, C₁-C₆alkyl or C₁-C₆-fluoroalkyl;    -   t is 0, 1, 2, 3, or 4;    -   X is absent, —O—, —S—, —S(═O)—, —S(═O)₂—, —C(═O)—, —CH₂—, —NH—        or —N(C₁-C₆alkyl)-.

In some embodiments, X is absent, O, S, —CH₂—, —C(═O)—, —NH—, or—N(C₁-C₄alkyl)-. In some other embodiments, X is O.

In some embodiments, the compound of Formula (V) has one of thefollowing structures:

wherein

-   -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₆heterocycloalkyl;    -   each R²³ is independently F or C₁-C₆-fluoroalkyl;    -   t is 1, 2, 3, or 4;    -   X is absent, O, S, —CH₂—, —C(═O)—, —NH—, or —N(C₁-C₄alkyl)-;    -   (h)Ar is a (hetero)aromatic ring, optionally substituted with        R¹¹² and R¹¹³;    -   R¹⁰² and R¹⁰³ are independently selected from H, F, Cl,        C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁴ and R¹⁰⁷ are independently selected from H, fluorine,        chlorine, C₁-C₂alkyl, —CF₃, or —CN;    -   R¹¹² is H, fluorine, chlorine, C₁-C₂alkyl, C₁-C₂alkoxy, —CN or        hydroxyl;    -   R¹¹³ is H, fluorine, chlorine, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁶ is H, hydroxyl, amine or C₁-C₆alkoxy;    -   R¹⁰⁶ and R¹⁰² may be linked to form a (hetero)aromatic ring        which is optionally substituted with fluorine, chlorine or        C₁-C₃alkyl;    -   R¹⁰⁵ is H, C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   V is —O—, —S—, —CH₂—, —CH(OH)—, —CH(C₁-C₃alkoxy)-, —C═CH₂,        carbonyl, —N—R¹¹⁶;    -   R¹¹⁵ is H, halogen, nitro, nitrile or C₁-C₆alkyl,        C₁-C₆cycloalkyl, optionally substituted with one or more        halogen;    -   R¹¹⁶ is H, C₁-C₄alkyl, C₁-C₄alkenyl, optionally substituted with        one or more halogen;    -   R¹²⁰ is C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   or a pharmaceutically acceptable salt thereof.

The term (h)Ar or (hetero)aromatic ring means an aromatic orheteroaromatic ring system, the aromatic skeleton of which contains fiveto ten atoms of which zero to four atoms other than carbon, are selectedfrom oxygen, nitrogen or sulfur. Examples are phenyl, naphthyl, pyridyl,thienyl, furanyl, thiazolyl, oxazolyl, pyrrolyl, thiadiazolyl,tetrazolyl, benzopyrrolyl and benzopyrrazolyl.

In another embodiment, the compound of Formula (V) has one of thefollowing structures:

wherein

-   -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₆heterocycloalkyl;    -   each R²³ is independently F or C₁-C₆-fluoroalkyl;    -   t is 1, 2, 3, or 4;    -   X is absent, O, S, —CH₂—, —C(═O)—, —NH—, or —N(C₁-C₄alkyl)-;    -   (h)Ar is a (hetero)aromatic ring, optionally substituted with        R¹¹² and R¹¹³;    -   R¹⁰² and R¹⁰³ are independently selected from H, F, Cl,        C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁴ and R¹⁰⁷ are independently selected from H, fluorine,        chlorine, C₁-C₂alkyl, —CF₃, or —CN;    -   R¹¹² is H, fluorine, chlorine, C₁-C₂alkyl, C₁-C₂alkoxy, —CN or        hydroxyl;    -   R¹¹³ is H, fluorine, chlorine, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁶ is H, hydroxyl, amine or C₁-C₆alkoxy;    -   R¹⁰⁶ and R¹⁰² may be linked to form a (hetero)aromatic ring        which is optionally substituted with fluorine, chlorine or        C₁-C₃alkyl;    -   R¹⁰⁵ is H, C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   V is —O—, —S—, —CH₂—, —CH(OH)—, —CH(C₁-C₃alkoxy)-, —C═CH₂,        carbonyl, —N—R¹¹⁶;    -   R¹¹⁵ is H, halogen, nitro, nitrile or C₁-C₆alkyl,        C₁-C₆cycloalkyl, optionally substituted with one or more        halogen;    -   R¹¹⁶ is H, C₁-C₄alkyl, C₁-C₄alkenyl, optionally substituted with        one or more halogen;    -   R¹²⁰ is C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula (V) has one of thefollowing structures:

wherein

-   -   R¹ is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R² is H, C₁-C₆alkyl, or C₁-C₆-fluoroalkyl;    -   R³ is C₁-C₆-fluoroalkyl;    -   or R² and R³ are taken together with the N atom to which they        are attached to form

-   -    is a monocyclic C₂-C₆heterocycloalkyl;    -   each R²³ is independently F or C₁-C₆-fluoroalkyl;    -   t is 1, 2, 3, or 4;    -   X is absent, —O—, —S—, —CH₂—, —C(═O)—, —NH—, or —N(C₁-C₄alkyl)-;    -   R¹⁰² and R¹⁰³ are independently selected from H, F, Cl,        C₁-C₃alkyl, C₁-C₃alkoxy, C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁴ and R¹⁰⁷ are independently selected from H, fluorine,        chlorine, C₁-C₂alkyl, —CF₃, or —CN;    -   R¹¹² is H, fluorine, chlorine, C₁-C₂alkyl, C₁-C₂alkoxy, —CN or        hydroxyl;    -   R¹¹³ is H, fluorine, chlorine, C₁-C₃alkyl, C₁-C₃alkoxy,        C₁-C₃alkylthio, —CF₃ or —CN;    -   R¹⁰⁶ is H, hydroxyl, amine or C₁-C₆alkoxy;    -   R¹⁰⁶ and R¹⁰² may be linked to form a (hetero)aromatic ring        which is optionally substituted with fluorine, chlorine or        C₁-C₃alkyl;    -   R¹⁰⁵ is H, C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   V is —O—, —S—, —CH₂—, —CH(OH)—, —CH(C₁-C₃alkoxy)-, —C═CH₂,        carbonyl, —N—R¹¹⁶;    -   R¹¹⁵ is H, halogen, nitro, nitrile or C₁-C₆alkyl,        C₁-C₆cycloalkyl, optionally substituted with one or more        halogen;    -   R¹¹⁶ is H, C₁-C₄alkyl, C₁-C₄alkenyl, optionally substituted with        one or more halogen;    -   R¹²⁰ is C₁-C₃alkyl, optionally substituted with one or more        fluorine;    -   or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (V) has one of thefollowing structures:

or is a pharmaceutically acceptable salt, or solvate, or prodrugthereof.Synthesis of Compounds

Compounds described herein are synthesized using standard synthetictechniques or using methods known in the art in combination with methodsdescribed herein. In additions, solvents, temperatures and otherreaction conditions presented herein may vary.

The starting material used for the synthesis of the compounds describedherein are either synthesized or obtained from commercial sources, suchas, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, AlfaAesar, and the like. The compounds described herein, and other relatedcompounds having different substituents are synthesized using techniquesand materials described herein or otherwise known, including those foundin March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey andSundberg, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum2000, 2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS3^(rd) Ed., (Wiley 1999). General methods for the preparation ofcompounds can be modified by the use of appropriate reagents andconditions for the introduction of the various moieties found in theformulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following Schemes.

Treatment of phenols of structure I with phenylacetic acids of structureII in the presence of a suitable Lewis Acid in a suitable solventprovides ketones of structure III. In some embodiments the suitableLewis Acid is BF₃-Et₂O. In some embodiments, the suitable solvent istoluene. In some embodiments, the reaction is heated. In someembodiments, the reaction is heated to 90° C. for 2 hours. Ketones ofstructure III are reacted with benzaldehydes of structure IV in thepresence of a suitable base and suitable solvent to provide compounds ofstructure V. In some embodiments, the suitable base is piperidine and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In some embodiments, thesuitable solvent is s-butanol and/or i-propanol. In some embodiments,ketones of structure III are reacted with benzaldehydes of structure IVin the presence of piperidine, DBU in s-butanol at reflux for 3 hoursand then i-propanol is added and the reaction is stirred at roomtemperature for 1-3 days. Compounds of structure V are treated withsuitable organometallic reagents to provide tertiary alcohols that arethen dehydrated to provide chromenes of structure VI. In someembodiments, the suitable organometallic reagent is R⁴—Li or R⁴—MgCl. Insome embodiments, the suitable organometallic reagent is methyl lithium,methyl magnesium chloride or methyl magnesium bromide. In someembodiments, compounds of structure V are dissolved in tetrahydrofuranand treated with methyl lithium at −78° C. to room temperature for 1hour or methyl magnesium chloride at 0° C. to room temperature for 2hours. The tertiary alcohol that is produced is then treated with aceticacid/water to eliminate to the chromene.

In some embodiments, benzaldehydes of structure IV are prepared asoutlined in Scheme 2.

In some embodiments, 4-hydroxybenzaldehydes of structure VIIa arecoupled with amino compounds of structure X under suitable couplingconditions. In some embodiments, the suitable coupling conditionsinclude the use of triphenylphosphine, diisopropyl azodicarboxylate andtetrahydrofuran. In some embodiments, the coupling is performed at roomtemperature.

In some embodiments, 4-halobenzaldehydes of structure VIIb (e.g. whereX1 is Br or I) or 4-fluorobenzaldehydes of structure VIII are coupledwith amino compounds of structure X under suitable coupling conditions.In some embodiments, when X¹ is I and X is O then the suitable reactioncondition include the use of CuI, potassium carbonate, butyronitrilewith heating to about 125° C. In an alternative embodiment, when X¹ is Iand X is O then the suitable reaction condition include the use of CuI,cesium carbonate, m-xylenes, with heating to about 125° C. In someembodiments, phenanthroline is used in these copper mediated couplingreaction conditions. In some embodiments, when X¹ is Br and X is N thenthe suitable reaction condition include the use of Pd₂(dba)₃, BINAP,cesium carbonate, and toluene, with heating to about 100° C. In someembodiments, when X¹ is Br and X is S then the suitable reactioncondition include the use of sodium hydride and dimethylformamide orcesium carbonate and N-methylpyrrolidinone with heating. In someembodiments, 4-fluorobenzaldehydes of structure VIII are coupled withamino compounds of structure X (where X is O) with the use of sodiumhydride and dimethylformamide or potassium tert-butoxide indimethylformamide. In some embodiments, 4-fluorobenzaldehydes ofstructure VIII are coupled with amino compounds of structure X (where Xis N) with the use of potassium carbonate and dimethylformamide withheating to reflux or potassium carbonate in ethanol with heating toreflux or the reaction is performed heated with heating. In someembodiments, 4-fluorobenzaldehydes of structure VIII are coupled withamino compounds of structure X (where X is S) with the use of sodiumhydride and dimethylformamide at room temperature.

In some embodiments, compounds are prepared as outlined in Scheme 3.

In some embodiments, ketones of structure III are prepared as outlinedin Scheme 1 and then reacted with 4-halobenzaldehydes of structure VIIdin the presence of a suitable base and suitable solvent to providecompounds of structure VIII. In some embodiments, the suitable base ispiperidine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). In someembodiments, the suitable solvent(s) is s-butanol and i-propanol.Compounds of structure VIII are then treated with suitableorganometallic reagents, followed by dehydration of the tertiary alcoholto provide chromenes of structure IX. In some embodiments, the suitableorganometallic reagent is R⁴—Li or MgCl—R⁴. In some embodiments,compounds of structure VIII are reacted with CsF and CF₃TMS in asuitable solvent at room temperature, followed by deprotection of theTMS protecting group and then dehydration of the resulting tertiaryalcohol to provide chromenes of structure IX where R⁴ is —CF₃. Chromenesof structure IX are then reacted with amino compounds of structure Xunder Ullmann reaction conditions to provide chromenes of structure VI.Ullmann reaction conditions include the use of copper salts. In someembodiments, the Ullmann reaction conditions include the use of CuI,Cs₂CO₃, and butyronitrile with heating to about 125° C. In someembodiments, the Ullmann reaction conditions include the use of CuI,bipyridine, and K₂CO₃ with heating to about 140° C. In some otherembodiments, Ullmann reaction conditions include the use of CuI,potassium carbonate, and butyronitrile with heating to about 125° C. forabout 5 days.

In an alternative embodiment, chromenes of structure IX are reacted withcompounds of structure XII under Ullmann reaction conditions, followedby conversion of the —OH to a suitable leaving group (LG¹) to providechromenes of structure XI. In some embodiments, X is O in the compoundsof structure XII and the Ullmann reaction conditions include the use ofCuI, potassium carbonate, and butyronitrile with heating to about 125°C. Examples of suitable leaving groups (LG1) include —Cl, —Br, —I, —OTf,—OMs, and —OTs. In some embodiments, the —OH is converted to —OMs bytreating the —OH with MsCl and triethylamine in dichloromethane at about0° C. In some embodiments, the —OH is converted to —OTf by treating the—OH with Tf₂O and triethylamine in dichloromethane at about −78° C. withwarming to room temperature.

Chromenes of structure XI are then treated with amines of structure XIIIunder suitable reaction conditions to provide chromenes of structure VI.In some embodiments, when LG¹ is —OMs then the suitable reactionconditions include the use of potassium carbonate, acetonitrile withheating to about 80° C. In some embodiments, when LG¹ is —OTf then thesuitable reaction conditions include the use of diisopropylethylamine,dichloromethane at about −78° C. with warming to room temperature.

In some embodiments, ketones of structure III are prepared as outlinedin Scheme 4:

Benzoic acid compounds of structure XI are converted to Weinreb amidesof structure XII. In some embodiments, benzoic acid compounds ofstructure XI are treated with oxalyl chloride, dimethylformamide (DMF),dichloromethane (DCM), at room temperature for 2 hours followed bytreatments with triethylamine (Et₃N), N,O-dimethylhydroxylamine-HCl,DCM, at 0° C. to rt for 1 hour to provide Weinreb amides of structureXII. Weinreb amides of structure XII are then treated with suitableorganometallics reagents of structure XIII to provide ketones ofstructure XIV. In some embodiments, R¹⁰⁰ is a phenol protecting group.In some embodiments, R¹⁰⁰ is methyl. In some embodiments, when R¹⁰⁰ ismethyl then ketones of structure XIV are treated with BBr₃, DCM, −78° C.to 0° C. for about 30 minutes to provide ketones of structure III.

In some embodiments, ketones of structure III are prepared as outlinedin Scheme 5:

In some embodiments, suitably protected phenols of structure XV aretreated with polyphosphoric acid and phenyl acetic acids of structure IIto provide ketones of structure XIV. In some embodiments, R¹⁰⁰ is aphenol protecting group. In some embodiments, R¹⁰⁰ is methyl. Ketones ofstructure XIV are then converted to ketones of structure III as outlinedin Scheme 4.

In some embodiments, ketones of structure III are prepared as outlinedin Scheme 6:

Alkyl esters of phenylacetic acids, such as compounds of structure XVII,are treated with a suitable base and then reacted with acid chlorides ofstructure XVI to provide keto-esters that are decarboxylated to provideketones of structure XIV. In some embodiments, R¹⁰⁰ is alkyl. In someembodiments, R¹⁰⁰ is methyl. In some embodiments, the suitable base islithium bis(trimethylsilyl)amide (LiHMDS). In some embodiments,compounds of structure XVII are treated with LiHMDS in tetrahydrofuranat −78° C. for about 15 minutes and then reacted with acid chlorides ofstructure XVI at −78° C. for about 1 hour. In some embodiments,decarboxylation of the keto-ester is accomplished using Krapchodecarboxylation condition. In some embodiments, Krapcho decarboxylationconditions include dimethylsulfoxide, brine with heating to about 150°C. for about 5 hours. Other decarboxylation conditions include the useof concentrated hydrochloric acid in ethanol at 130° C. for about 3hours. R¹⁰⁰ is then removed from ketones of structure XIV as describedin Scheme 4 to provide ketones of structure III.

In some embodiments, when R² and R³ are taken together with the N atomto which they are attached to form a substituted or unsubstitutedheterocycle, the substituted or unsubstituted heterocycle is prepared asoutlined in Scheme 7.

In some embodiments, substituted or unsubstituted heterocycles ofstructure XXI, where R³⁰⁰ is a protecting group such as t-BOC or Cbz,are first deprotected and then reacted with compounds of structure XX,where LG¹ is a leaving group, under suitable reaction conditions toprovide compounds of structure XXII. In some embodiments, when R³⁰⁰ ist-BOC then the deprotection is performed using hydrochloric acid indioxane at room temperature. In some embodiments, when LG¹ is —OMs thenthe suitable reaction conditions include the use of potassium carbonate(or cesium carbonate), acetonitrile (or methanol, ethanol, isopropanol,or tetrahydrofuran) with optional heating. In some embodiments, when LG¹is —OMs then the suitable reaction conditions include performing thereaction neat (i.e. amine as solvent) with heating. In some embodiments,when LG¹ is —OTf then the suitable reaction conditions include the useof diisopropylethylamine, dichloromethane, with the reaction initialperformed at −78° C. then warming to room temperature. In someembodiments, R²⁰⁰ is a suitable protecting group for X. In someembodiments, X is oxygen. In some embodiments, R²⁰⁰ is trityl or benzyl.In some embodiments, R²⁰⁰ is removed from compounds of structure XXII toprovide compounds of structure XXVII. In some embodiments, the suitabledeprotection conditions include the use of hydrochloric acid in dioxane(or tetrahydrofuran); or formic acid in diethylether; or acetic acidether (for when R²⁰⁰ is trityl).

Alternatively, reaction of amines of structure XXV with activatedalkanes of structure XXVI, where LG² is a suitable leaving group, undersuitable reaction conditions provides compounds of structure XXII.Suitable leaving groups include, chloro, bromo, iodo, tosylate,mesylate, and triflate. In some embodiments, suitable reactionconditions include potassium carbonate, acetonitrile or neat, at roomtemperature.

Alternatively, reaction of diacids of structure XXIV, with aceticanhydride at about 85° C. for about 30 minutes provides an anhydridewhich is then treated with amines of structure XXV followed by aceticanhydride to provide amides of structure XXIII. Amides of structureXXIII are then reduced to provide amines of structure XXII. In someembodiment, the reduction is performed with lithium aluminum hydride intetrahydrofuran LiAlH₄, THF or DIBAL, THF.

In some embodiments, amines of structure XXV are reacted with compoundsof structure XXX under suitable reaction conditions to provide compoundsof structure XXIX. In some embodiments, the suitable reaction conditionsinclude the use of potassium carbonate in tetrahydrofuran ordimethylformamide. In some embodiment, amides of structure XXIX are thenreduced to provide amines of structure XXII as described above.

In some embodiments, fluorinated R¹ groups are introduced as outlined inScheme 8.

R²⁰⁰ is a suitable protecting group for the oxygen atom. In someembodiments, R²⁰⁰ is trityl. R³⁰⁰ is a suitable protecting group for thenitrogen atom. In some embodiments, R³⁰⁰ is mesyl, tosyl or Cbz. In someembodiments, R²⁰⁰ and R³⁰⁰ are taken together with oxygen and nitrogenatoms to which they are attached to form a cyclic protecting group. Insome cases the protected amino-alcohol is an oxazolidine such as that inGarner's aldehyde.

In some embodiments, esters of structure XXXI are reduced under suitablereaction conditions to provide alcohols of structure XXXII. In someembodiments, the suitable reduction reaction conditions include the usesodium borohydride in tetrahydrofuran or DIBAL-H in tetrahydrofuran.Oxidation of the alcohol under suitable oxidation conditions providesaldehydes of structure XXXIII. Exemplary oxidation conditions includeDess-Martin periodinane, Swern oxidation, or PDC.

Treatment of alcohols of structure XXXII with a suitable fluorinatingagent provides monofluoro compounds of structure XXXIV. In someembodiments, such suitable fluorinating conditions include the use ofdiethylaminosulfur trifluoride (DAST) in dichloromethane at about −78°C. with warming to room temperature. Alternatively, the suitablefluorinating reaction conditions include the use ofbis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-fluor) indichloromethane at about −78° C. with warming to room temperature. Inyet in another alternative embodiment, the suitable fluorinatingreaction conditions include the use of SF₄, HF. In yet anotherembodiment, the suitable fluorinating reaction conditions include theuse methane sulfonyl chloride, triethylamine, in dichloromethane atabout 0° C. followed by tetrabutyammonium fluoride.

In some embodiments, alcohols of structure XXXII are used to preparetrifluoro compounds of structure XXXVI. In some embodiments, alcohols ofstructure XXXII are oxidized with PDC or potassium permanganate and thentreated with SF₄, HF to provide trifluoro compounds of structure XXXVI.

In some embodiments, aldehydes of structure XXXIII are used to preparedifluoro compounds of structure XXXVIII. In some embodiments, aldehydesof structure XXXIII are treated with diethylaminosulfur trifluoride(DAST) in dichloromethane at about −78° C. with warming to roomtemperature. In some other embodiments, aldehydes of structure XXXIIIare treated with bis(2-methoxyethyl)aminosulfur trifluoride(Deoxo-fluor) in dichloromethane at about −78° C. with warming to roomtemperature.

R³⁰⁰ is removed under suitable deprotection reaction conditions. In someembodiments, when R³⁰⁰ is Ms or Ts then the suitable deprotectionreaction conditions include the use of sodium hydroxide, and water withheating. In some embodiment, when R³⁰⁰ is Cbz then the suitabledeprotection reaction conditions include the use of hydrogen gas andpalladium on carbon.

In some embodiments, fluorinated R²³ groups are introduced as outlinedin Scheme 9.

Treatment of alcohols of structure XXXX with a suitable fluorinatingagent under suitable reaction conditions provides monofluoro compoundsof structure XXXXI. In some embodiments, the suitable fluorinating isdiethylaminosulfur trifluoride (DAST) and the suitable reactionconditions includes the use dichloromethane at about −78° C. withwarming to room temperature. In some other embodiments, the suitablefluorinating is SF₄, HF. In an alternative embodiment, alcohols ofstructure XXXX are treated with methane sulfonyl chloride andtriethylamine in dichloromethane at about 0° C. followed bytetrabutyammonium fluoride to provide monofluoro compounds of structureXXXXI.

Oxidation of alcohols of structure XXXX provides aldehydes of structureXXXXII, which are then treated with diethylaminosulfur trifluoride(DAST) in dichloromethane at about −78° C. with warming to roomtemperature to provide difluoro compounds of structure XXXXIII. In someother embodiments, aldehydes of structure XXXXII are treated withbis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-fluor) indichloromethane at about −78° C. with warming to room temperature toprovide difluoro compounds of structure XXXXIII.

Trifluoro compounds of structure XXXXV are prepared from acids ofstructure XXXXIV or aldehydes of structure XXXXII. In some embodiments,acids of structure XXXXIV are treated with diethylaminosulfurtrifluoride (DAST) in dichloromethane at about −78° C. with warming toroom temperature to provide trifluoro compounds of structure XXXXV. Insome other embodiments, acids of structure XXXXIV are treated withbis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-fluor) indichloromethane at about −78° C. with warming to room temperature toprovide trifluoro compounds of structure XXXXV. In some embodiments,aldehydes of structure XXXXII are treated with propane-1,3-dithiol,BF₃—OEt₂ in dichloromethane followed by pyridine, hydrofluoride (1:9),dibromodimethylhydantoin in dichloromethane at 0° C. to providetrifluoro compounds of structure XXXXV.

In some embodiments, monofluoro compounds of structure XXXXI areelaborated into compounds of structure XXXXVII or XXXXIX as shown inScheme 10. Although monofluoro compounds are shown, it is understoodthat the same transformation could be used for other fluorinatedcompounds.

In some embodiment, when R³⁰⁰ is t-Boc, then monofluoro compounds ofstructure XXXXI are treated with hydrochloric acid in dioxane at roomtemperature to provide amines of structure XXXXVI. Amines of structureXXXXVI are then coupled with compounds of structure XX and the R²⁰⁰protecting group is removed as outlined in Scheme 7. In someembodiments, amines of structure XXXXVI are treated with bromoethanoland potassium carbonate in acetonitrile with heating to about 80° C. Inother embodiments, amines of structure XXXXVI are treated withbromoethanol and potassium carbonate in ethanol with heating to about80° C.

In one aspect, compounds described herein are synthesized as outlined inthe Examples.

Throughout the specification, groups and substituents thereof are chosenby one skilled in the field to provide stable moieties and compounds.

A detailed description of techniques applicable to the creation ofprotecting groups and their removal are described in Greene and Wuts,Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, NewYork, N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, NewYork, N.Y., 1994, which are incorporated herein by reference for suchdisclosure.

Further Forms of Compounds

In one aspect, compounds described herein possess one or morestereocenters and each stereocenter exists independently in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. The compounds and methods provided hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the appropriate mixtures thereof. In certainembodiments, compounds described herein are prepared as their individualstereoisomers by reacting a racemic mixture of the compound with anoptically active resolving agent to form a pair of diastereoisomericcompounds/salts, separating the diastereomers and recovering theoptically pure enantiomers. In some embodiments, resolution ofenantiomers is carried out using covalent diastereomeric derivatives ofthe compounds described herein. In another embodiment, diastereomers areseparated by separation/resolution techniques based upon differences insolubility. In other embodiments, separation of stereoisomers isperformed by chromatography or by the forming diastereomeric salts andseparation by recrystallization, or chromatography, or any combinationthereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers,Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In someembodiments, stereoisomers are obtained by stereoselective synthesis.

The methods and compositions described herein include the use ofamorphous forms as well as crystalline forms (also known as polymorphs).In one aspect, compounds described herein are in the form ofpharmaceutically acceptable salts. As well, active metabolites of thesecompounds having the same type of activity are included in the scope ofthe present disclosure. In addition, the compounds described herein canexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. In some embodiments,the design of a prodrug increases the effective water solubility. Anexample, without limitation, of a prodrug is a compound describedherein, which is administered as an ester (the “prodrug”) but then ismetabolically hydrolyzed to provide the active entity. In someembodiments, the active entity is a phenolic compound as describedherein. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound.

Prodrugs of the compounds described herein include, but are not limitedto, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives,N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines,N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters,and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A.Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.;Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design andApplication of Prodrugs” in A Textbook of Drug Design and Development,Krosgaard-Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; andBundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each ofwhich is incorporated herein by reference. In some embodiments, ahydroxyl group in the compounds disclosed herein is used to form aprodrug, wherein the hydroxyl group is incorporated into an acyloxyalkylester, alkoxycarbonyloxyalkyl ester, alkyl ester, aryl ester, phosphateester, sugar ester, ether, and the like.

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a compound of Formula (I), (II), (III),(IV), (V), or (VI), as set forth herein are included within the scope ofthe claims. In some cases, some of the herein-described compounds may bea prodrug for another derivative or active compound.

In some embodiments, sites on the aromatic ring portion of compoundsdescribed herein are susceptible to various metabolic reactions.Incorporation of appropriate substituents on the aromatic ringstructures will reduce, minimize or eliminate this metabolic pathway. Inspecific embodiments, the appropriate substituent to decrease oreliminate the susceptibility of the aromatic ring to metabolic reactionsis, by way of example only, a halogen, deuterium or an alkyl group.

In another embodiment, the compounds described herein are labeledisotopically (e.g. with a radioisotope) or by another other means,including, but not limited to, the use of chromophores or fluorescentmoieties, bioluminescent labels, or chemiluminescent labels.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulae and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, forexample, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl. In one aspect,isotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. In oneaspect, substitution with isotopes such as deuterium affords certaintherapeutic advantages resulting from greater metabolic stability, suchas, for example, increased in vivo half-life or reduced dosagerequirements. In some embodiments, one or more hydrogen atoms that arepresent in the compounds described herein is replaced with one or moredeuterium atoms.

In additional or further embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

“Pharmaceutically acceptable,” as used herein, refers a material, suchas a carrier or diluent, which does not abrogate the biological activityor properties of the compound, and is relatively nontoxic, i.e., thematerial may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In some embodiments, pharmaceuticallyacceptable salts are obtained by reacting a compound described hereinwith acids. Pharmaceutically acceptable salts are also obtained byreacting a compound described herein with a base to form a salt.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid to form a salt such as, for example, ahydrochloric acid salt, a hydrobromic acid salt, a sulfuric acid salt, aphosphoric acid salt, a metaphosphoric acid salt, and the like; or withan organic acid to form a salt such as, for example, an acetic acidsalt, a propionic acid salt, a hexanoic acid salt, acyclopentanepropionic acid salt, a glycolic acid salt, a pyruvic acidsalt, a lactic acid salt, a malonic acid salt, a succinic acid salt, amalic acid salt, a maleic acid salt, a fumaric acid salt, atrifluoroacetic acid salt, a tartaric acid salt, a citric acid salt, abenzoic acid salt, a 3-(4-hydroxybenzoyl)benzoic acid salt, a cinnamicacid salt, a mandelic acid salt, a methanesulfonic acid salt, anethanesulfonic acid salt, a 1,2-ethanedisulfonic acid salt, a2-hydroxyethanesulfonic acid salt, a benzenesulfonic acid salt, atoluenesulfonic acid salt, a 2-naphthalenesulfonic acid salt, a4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid salt, a glucoheptonicacid salt, a 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid) salt,a 3-phenylpropionic acid salt, a trimethylacetic acid salt, a tertiarybutylacetic acid salt, a lauryl sulfuric acid salt, a gluconic acidsalt, a glutamic acid salt, a hydroxynaphthoic acid salt, a salicylicacid salt, a stearic acid salt, a muconic acid salt, a butyric acidsalt, a phenylacetic acid salt, a phenylbutyric acid salt, a valproicacid salt, and the like; (2) salts formed when an acidic proton presentin the parent compound is replaced by a metal ion, e.g., an alkali metalion (e.g. a lithium salt, a sodium salt, or a potassium salt), analkaline earth ion (e.g. a magnesium salt, or a calcium salt), or analuminum ion (e.g. an aluminum salt). In some cases, compounds describedherein may coordinate with an organic base to form a salt, such as, butnot limited to, an ethanolamine salt, a diethanolamine salt, atriethanolamine salt, a tromethamine salt, a N-methylglucamine salt, adicyclohexylamine salt, or a tris(hydroxymethyl)methylamine salt. Inother cases, compounds described herein may form salts with amino acidssuch as, but not limited to, an arginine salt, a lysine salt, and thelike. Acceptable inorganic bases used to form salts with compounds thatinclude an acidic proton, include, but are not limited to, aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate,sodium hydroxide, and the like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent, andmay be formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and thelike. Hydrates are formed when the solvent is water, or alcoholates areformed when the solvent is alcohol. Solvates of compounds describedherein can be conveniently prepared or formed during the processesdescribed herein. In addition, the compounds provided herein can existin unsolvated as well as solvated forms.

Certain Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Unlessotherwise indicated, conventional methods of mass spectroscopy, NMR,HPLC, protein chemistry, biochemistry, recombinant DNA techniques andpharmacology are employed. In this application, the use of “or” or “and”means “and/or” unless stated otherwise. Furthermore, use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described.

An “alkyl” group refers to an aliphatic hydrocarbon group. The alkylgroup is saturated or unsaturated. The alkyl moiety, whether saturatedor unsaturated, may be branched or straight chain. The “alkyl” group mayhave 1 to 6 carbon atoms (whenever it appears herein, a numerical rangesuch as “1 to 6” refers to each integer in the given range; e.g., “1 to6 carbon atoms” means that the alkyl group may consist of 1 carbon atom,2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbonatoms, although the present definition also covers the occurrence of theterm “alkyl” where no numerical range is designated). In one aspect thealkyl is selected from the group consisting of methyl, ethyl, propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkylgroups include, but are in no way limited to, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl,neopentyl, hexyl, allyl, vinyl, acetylene, but-2-enyl, but-3-enyl, andthe like. In some embodiments, 1 or more hydrogen atoms of an alkyl arereplaced with 1 or more deuterium atoms.

The term “alkylene” refers to a divalent alkyl radical. Any of the abovementioned monovalent alkyl groups may be an alkylene by abstraction of asecond hydrogen atom from the alkyl. Typical alkylene groups include,but are not limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and the like.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from the group x=1, y=1 and x=2, y=0.

The term “aromatic” refers to a planar ring having a delocalizedm-electron system containing 4n+2 π electrons, where n is an integer.Aromatics are optionally substituted. The term “aromatic” includes bothcarbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or“heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The termincludes monocyclic or fused-ring polycyclic (i.e., rings which shareadjacent pairs of carbon atoms) groups.

The term “carbocyclic” or “carbocycle” refers to a ring or ring systemwhere the atoms forming the backbone of the ring are all carbon atoms.The term thus distinguishes carbocyclic from heterocyclic rings in whichthe ring backbone contains at least one atom which is different fromcarbon.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl groups areoptionally substituted. In one aspect, an aryl is a phenyl or anaphthalenyl. In one aspect, an aryl is a phenyl. In one aspect, an arylis a C₆-C₁₀aryl. Depending on the structure, an aryl group can be amonoradical or a diradical (i.e., an arylene group). In someembodiments, 1 or more hydrogen atoms of an aryl are replaced with 1 ormore deuterium atoms

The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic,non-aromatic radical, wherein each of the atoms forming the ring (i.e.skeletal atoms) is a carbon atom. Cycloalkyls may be saturated, orpartially unsaturated. Cycloalkyls may be fused with an aromatic ring,and the point of attachment is at a carbon that is not an aromatic ringcarbon atom. Cycloalkyl groups include groups having from 3 to 10 ringatoms. In some embodiments, cycloalkyl groups are selected from amongcyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups may besubstituted or unsubstituted. Depending on the structure, a cycloalkylgroup can be a monoradical or a diradical (i.e., an cycloalkylene group,such as, but not limited to, cyclopropan-1,1-diyl, cyclobutan-1,1-diyl,cyclopentan-1,1-diyl, cyclohexan-1,1-diyl, cyclohexan-1,4-diyl,cycloheptan-1,1-diyl, and the like). In one aspect, a cycloalkyl is aC₃-C₆cycloalkyl.

The term “halo” or, alternatively, “halogen” or “halide” means fluoro(F), chloro (Cl), bromo (Br) or iodo (I). In some embodiments, halogenis F or Cl. In some embodiments, halogen is F.

The term “fluoroalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by a fluorine atom. In one aspect, a fluoralkyl is aC₁-C₆-fluoroalkyl. In some embodiments, a fluoroalkyl is amonofluoroalkyl, wherein one hydrogen atom of the alkyl is replaced by afluorine atom. In some embodiments, a fluoroalkyl is a difluoroalkyl,wherein two hydrogen atoms of the alkyl are replaced by a fluorine atom.In some embodiments, a fluoroalkyl is a trifluoroalkyl, wherein threehydrogen atom of the alkyl are replaced by a fluorine atom. In someembodiments, a fluoroalkyl is a monofluoroalkyl, difluoroalkyl, ortrifluoroalkyl. In some embodiments, a monofluoroalkyl is —CH₂F, —CHF₂,—CF₃, —CHFCH₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,—CHCH₃CF₃, —CH(CF₃)₂, or —CF(CH₃)₂.

The term “fluoroalkylene” refers to a divalent fluoroalkyl radical. Anyof the above mentioned monovalent fluoroalkyl groups may be anfluoroalkylene by abstraction of a second hydrogen atom from thefluoroalkyl. Typical alkylene groups include, but are not limited to,—CF₂—, CHF—, —CH(CF₃)—, —C(CF₃)₂—, —CHFCH₂—, —CH₂CHF—, —CF₂CH₂—,—CH₂CF₂—, —CH₂CH(CF₃)—, —CH₂CH(CHF₂)—, —CH₂CH(CFH₂)— and the like.

The term “heteroalkyl” refers to an alkyl group in which one or moreskeletal atoms of the alkyl are selected from an atom other than carbon,e.g., oxygen, nitrogen (e.g. —NH—, —N(alkyl)-), sulfur, or combinationsthereof. In one aspect, a heteroalkyl is a C₁-C₆heteroalkyl. In someembodiments, a heteroalkyl is a C₁-C₄heteroalkyl. In some embodiments, aheteroalkyl is an alkyl group in which one or more skeletal atoms of thealkyl is oxygen (e.g. a hydroxyalkyl or an alkoxyalkyl).

The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings(also known as heteroaryls) and heterocycloalkyl rings (also known asheteroalicyclic groups) containing one to four heteroatoms in thering(s), where each heteroatom in the ring(s) is selected from O, S andN, wherein each heterocyclic group has from 4 to 10 atoms in its ringsystem, and with the proviso that the any ring does not contain twoadjacent O or S atoms. Non-aromatic heterocyclic groups (also known asheterocycloalkyls) include groups having only 3 atoms in their ringsystem, but aromatic heterocyclic groups must have at least 5 atoms intheir ring system. The heterocyclic groups include benzo-fused ringsystems. An example of a 3-membered heterocyclic group is aziridinyl. Anexample of a 4-membered heterocyclic group is azetidinyl. An example ofa 5-membered heterocyclic group is thiazolyl. An example of a 6-memberedheterocyclic group is pyridyl, and an example of a 10-memberedheterocyclic group is quinolinyl. Examples of non-aromatic heterocyclicgroups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl,homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl,thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl,indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl,pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl,dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl,3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl andquinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl,imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl,furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl,cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl,triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl,furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl,benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, andfuropyridinyl. The foregoing groups may be C-attached (or C-linked) orN-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl orimidazol-3-yl (both N-attached) or imidazol-2-yl, imidazol-4-yl orimidazol-5-yl (all C-attached). The heterocyclic groups includebenzo-fused ring systems. Non-aromatic heterocycles may be substitutedwith one or two oxo (═O) moieties, such as pyrrolidin-2-one.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groupsinclude the following moieties:

and the like. Monocyclic heteroaryls include pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl,pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Insome embodiments, a heteroaryl contains 0-3 N atoms in the ring. In someembodiments, a heteroaryl contains 1-3 N atoms in the ring. In someembodiments, a heteroaryl contains 0-3 N atoms, 0-1 O atoms, and 0-1 Satoms in the ring. In some embodiments, a heteroaryl is a monocyclic orbicyclic heteroaryl. In some embodiments, heteroaryl is aC₁-C₉heteroaryl. In some embodiments, monocyclic heteroaryl is aC₁-C₅heteroaryl. In some embodiments, monocyclic heteroaryl is a5-membered or 6-membered heteroaryl. In some embodiments, bicyclicheteroaryl is a C₆-C₉heteroaryl. Depending on the structure, aheteroaryl group can be a monoradical or a diradical (i.e., aheteroarylene group).

A “heterocycloalkyl” or “heteroalicyclic” group refers to a cycloalkylgroup wherein at least one of the carbon atoms of the cycloalkyl isreplaced with nitrogen (unsubstituted or substituted, e.g. —NH—,—NR²³—), oxygen (—O—), or sulfur (e.g. —S—, —S(═O)— or —S(═O)₂—). Theradicals may be fused with an aryl or heteroaryl. In some embodiments,the heterocycloalkyl is selected from oxazolidinonyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, and indolinyl. The term heteroalicyclic also includes allring forms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. In oneaspect, a heterocycloalkyl is a C₂-C₁₀heterocycloalkyl. In anotheraspect, a heterocycloalkyl is a C₄-C₁₀heterocycloalkyl. In someembodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. Insome embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atomsand 0-1 S atoms in the ring.

The term “bond” or “single bond” refers to a chemical bond between twoatoms, or two moieties when the atoms joined by the bond are consideredto be part of larger substructure. In one aspect, when a group describedherein is a bond, the referenced group is absent thereby allowing a bondto be formed between the remaining identified groups.

The term “moiety” refers to a specific segment or functional group of amolecule. Chemical moieties are often recognized chemical entitiesembedded in or appended to a molecule.

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from alkyl, cycloalkyl, aryl,heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, alkylthio,arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone,cyano, halo, nitro, haloalkyl, fluoroalkyl, fluoroalkoxy, and amino,including mono- and di-substituted amino groups, and the protectedderivatives thereof. In some embodiments, optional substituents areindependently selected from halogen, —CN, —NH₂, —NH(CH₃), —N(CH₃)₂, —OH,—CO₂H, —CO₂alkyl, —C(═O)NH₂, —C(═O)NH(alkyl), —C(═O)N(alkyl)₂,—S(═O)₂NH₂, —S(═O)₂NH(alkyl), —S(═O)₂N(alkyl)₂, alkyl, cycloalkyl,fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl,heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,alkylsulfone, and arylsulfone. In some embodiments, optionalsubstituents are independently selected from halogen, —CN, —NH₂, —OH,—NH(CH₃), —N(CH₃)₂, —CH₃, —CH₂CH₃, —CF₃, —OCH₃, and —OCF₃. In someembodiments, substituted groups are substituted with one or two of thepreceding groups. In some embodiments, an optional substituent on analiphatic carbon atom (acyclic or cyclic, saturated or unsaturatedcarbon atoms, excluding aromatic carbon atoms) includes oxo (═O).

In certain embodiments, the compounds presented herein possess one ormore stereocenters and each center independently exists in either the Ror S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Stereoisomers are obtained, if desired, bymethods such as, stereoselective synthesis and/or the separation ofstereoisomers by chiral chromatographic columns.

The methods and formulations described herein include the use ofN-oxides (if appropriate), crystalline forms (also known as polymorphs),or pharmaceutically acceptable salts of compounds having the structureof Formula (I), (II), (III), (IV), (V), or (VI), as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. In specificembodiments, the compounds described herein exist in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. In other embodiments, the compounds described herein exist inunsolvated form.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “modulate” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator” as used herein, refers to a molecule that interactswith a target either directly or indirectly. The interactions include,but are not limited to, the interactions of an agonist, partial agonist,an inverse agonist, antagonist, degrader, or combinations thereof. Insome embodiments, a modulator is an antagonist. In some embodiments, amodulator is a degrader.

“Selective estrogen receptor modulator” or “SERM” as used herein, refersto a molecule that differentially modulates the activity of estrogenreceptors in different tissues. For example, in some embodiments, a SERMdisplays ER antagonist activity in some tissues and ER agonist activityin other tissues. In some embodiments, a SERM displays ER antagonistactivity in some tissues and minimal or no ER agonist activity in othertissues. In some embodiments, a SERM displays ER antagonist activity inbreast tissues, ovarian tissues, endometrial tissues, and/or cervicaltissues but minimal or no ER agonist activity in uterine tissues.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “degrader” as used herein, refers to a small molecule agentthat binds to a nuclear hormone receptor and subsequently lowers thesteady state protein levels of said receptor. In some embodiments, adegrader as described herein lowers steady state estrogen receptorlevels by at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90% or at least 95%. In someembodiments, a degrader as described herein lowers steady state estrogenreceptor levels by at least 65%. In some embodiments, a degrader asdescribed herein lowers steady state estrogen receptor levels by atleast 85%.

The term “selective estrogen receptor degrader” or “SERD” as usedherein, refers to a small molecule agent that preferentially binds toestrogen receptors versus other receptors and subsequently lowers thesteady state estrogen receptor levels.

The term “ER-dependent”, as used herein, refers to diseases orconditions that would not occur, or would not occur to the same extent,in the absence of estrogen receptors.

The term “ER-mediated”, as used herein, refers to diseases or conditionsthat would not occur in the absence of estrogen receptors but can occurin the presence of estrogen receptors.

The term “ER-sensitive”, as used herein, refers to diseases orconditions that would not occur, or would not occur to the same extent,in the absence of estrogens.

The term “cancer” as used herein refers to an abnormal growth of cellswhich tend to proliferate in an uncontrolled way and, in some cases, tometastasize (spread). The types of cancer include, but is not limitedto, solid tumors (such as those of the bladder, bowel, brain, breast,endometrium, heart, kidney, lung, uterus, lymphatic tissue (lymphoma),ovary, pancreas or other endocrine organ (thyroid), prostate, skin(melanoma or basal cell cancer) or hematological tumors (such as theleukemias and lymphomas) at any stage of the disease with or withoutmetastases.

Additional non-limiting examples of cancers include, acute lymphoblasticleukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer,appendix cancer, astrocytomas, atypical teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer(osteosarcoma and malignant fibrous histiocytoma), brain stem glioma,brain tumors, brain and spinal cord tumors, breast cancer, bronchialtumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia,chronic myelogenous leukemia, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-Cell lymphoma, embryonal tumors,endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer,ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladdercancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumor (GIST), gastrointestinal stromal celltumor, germ cell tumor, glioma, hairy cell leukemia, head and neckcancer, hepatocellular (liver) cancer, hodgkin lymphoma, hypopharyngealcancer, intraocular melanoma, islet cell tumors (endocrine pancreas),Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngealcancer, leukemia, Acute lymphoblastic leukemia, acute myeloid leukemia,chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cellleukemia, liver cancer, lung cancer, non-small cell lung cancer, smallcell lung cancer, Burkitt lymphoma, cutaneous T-cell lymphoma, Hodgkinlymphoma, non-Hodgkin lymphoma, lymphoma, Waldenström macroglobulinemia,medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouthcancer, chronic myelogenous leukemia, myeloid leukemia, multiplemyeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,non-small cell lung cancer, oral cancer, oropharyngeal cancer,osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer,ovarian epithelial cancer, ovarian germ cell tumor, ovarian lowmalignant potential tumor, pancreatic cancer, papillomatosis,parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymaltumors of intermediate differentiation, pineoblastoma and supratentorialprimitive neuroectodermal tumors, pituitary tumor, plasma cellneoplasm/multiple myeloma, pleuropulmonary blastoma, primary centralnervous system lymphoma, prostate cancer, rectal cancer, renal cell(kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary glandcancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, kaposi, Sézarysyndrome, skin cancer, small cell Lung cancer, small intestine cancer,soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer,supratentorial primitive neuroectodermal tumors, T-cell lymphoma,testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroidcancer, urethral cancer, uterine cancer, uterine sarcoma, vaginalcancer, vulvar cancer, Waldenström macroglobulinemia, Wilms tumor.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in disease symptoms. Anappropriate “effective” amount in any individual case may be determinedusing techniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, and a co-agent, areboth administered to a patient simultaneously in the form of a singleentity or dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The terms “kit” and “article of manufacture” are used as synonyms.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes) by which a particular substance is changed by anorganism. Thus, enzymes may produce specific structural alterations to acompound. For example, cytochrome P450 catalyzes a variety of oxidativeand reductive reactions while uridine diphosphate glucuronyltransferasescatalyze the transfer of an activated glucuronic-acid molecule toaromatic alcohols, aliphatic alcohols, carboxylic acids, amines and freesulphydryl groups. Metabolites of the compounds disclosed herein areoptionally identified either by administration of compounds to a hostand analysis of tissue samples from the host, or by incubation ofcompounds with hepatic cells in vitro and analysis of the resultingcompounds.

The term “subject” or “patient” encompasses mammals. Examples of mammalsinclude, but are not limited to, any member of the Mammalian class:humans, non-human primates such as chimpanzees, and other apes andmonkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. In one aspect, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating at least one symptom of a diseaseor condition, preventing additional symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition eitherprophylactically and/or therapeutically.

Routes of Administration

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

Pharmaceutical Compositions/Formulations

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. Pharmaceutical compositions are formulatedin a conventional manner using one or more pharmaceutically acceptableinactive ingredients that facilitate processing of the active compoundsinto preparations that can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein can be found, for example,in Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference for such disclosure.

Provided herein are pharmaceutical compositions that include a compoundof Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableinactive ingredient. In some embodiments, the compounds described hereinare administered as pharmaceutical compositions in which a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, is mixed with other active ingredients, as incombination therapy. In other embodiments, the pharmaceuticalcompositions include other medicinal or pharmaceutical agents, carriers,adjuvants, preserving, stabilizing, wetting or emulsifying agents,solution promoters, salts for regulating the osmotic pressure, and/orbuffers. In yet other embodiments, the pharmaceutical compositionsinclude other therapeutically valuable substances.

A pharmaceutical composition, as used herein, refers to a mixture of acompound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, with other chemical components(i.e. pharmaceutically acceptable inactive ingredients), such ascarriers, excipients, binders, filling agents, suspending agents,flavoring agents, sweetening agents, disintegrating agents, dispersingagents, surfactants, lubricants, colorants, diluents, solubilizers,moistening agents, plasticizers, stabilizers, penetration enhancers,wetting agents, anti-foaming agents, antioxidants, preservatives, or oneor more combination thereof. The pharmaceutical composition facilitatesadministration of the compound to a mammal.

A therapeutically effective amount can vary widely depending on theseverity of the disease, the age and relative health of the subject, thepotency of the compound used and other factors. The compounds can beused singly or in combination with one or more therapeutic agents ascomponents of mixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical formulations described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, are manufactured in a conventional manner, such as, by way ofexample only, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

The pharmaceutical compositions will include at least one compound ofFormula (I), (II), (III), (IV), (V), or (VI), as an active ingredient infree-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides (if appropriate), crystalline forms,amorphous phases, as well as active metabolites of these compoundshaving the same type of activity. In some embodiments, compoundsdescribed herein exist in unsolvated form or in solvated forms withpharmaceutically acceptable solvents such as water, ethanol, and thelike. The solvated forms of the compounds presented herein are alsoconsidered to be disclosed herein.

The pharmaceutical compositions described herein, which include acompound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, are formulated into anysuitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions,solid oral dosage forms, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical preparations that are administered orally includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules contain the active ingredients in admixture with filler such aslactose, binders such as starches, and/or lubricants such as talc ormagnesium stearate and, optionally, stabilizers. In some embodiments,the push-fit capsules do not include any other ingredient besides thecapsule shell and the active ingredient. In soft capsules, the activecompounds are dissolved or suspended in suitable liquids, such as fattyoils, liquid paraffin, or liquid polyethylene glycols. In someembodiments, stabilizers are added.

All formulations for oral administration are in dosages suitable forsuch administration.

In one aspect, solid oral soage forms are prepared by mixing a compoundof Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, with one or more of the following:antioxidants, flavoring agents, and carrier materials such as binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, and diluents.

In some embodiments, the solid dosage forms disclosed herein are in theform of a tablet, (including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder, a capsule, soliddispersion, solid solution, bioerodible dosage form, controlled releaseformulations, pulsatile release dosage forms, multiparticulate dosageforms, beads, pellets, granules. In other embodiments, thepharmaceutical formulation is in the form of a powder. In still otherembodiments, the pharmaceutical formulation is in the form of a tablet.In other embodiments, pharmaceutical formulation is in the form of acapsule.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, with one or more pharmaceutical excipients toform a bulk blend composition. The bulk blend is readily subdivided intoequally effective unit dosage forms, such as tablets, pills, andcapsules. In some embodiments, the individual unit dosages include filmcoatings. These formulations are manufactured by conventionalformulation techniques.

Conventional formulation techniques include, e.g., one or a combinationof methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dryor non-aqueous granulation, (5) wet granulation, or (6) fusion. Othermethods include, e.g., spray drying, pan coating, melt granulation,granulation, fluidized bed spray drying or coating (e.g., wurstercoating), tangential coating, top spraying, tableting, extruding and thelike.

In some embodiments, tablets will include a film surrounding the finalcompressed tablet. In some embodiments, the film coating can provide adelayed release of the compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, from theformulation. In other embodiments, the film coating aids in patientcompliance (e.g., Opadry® coatings or sugar coating). Film coatingsincluding Opadry® typically range from about 1% to about 3% of thetablet weight.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound described above, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule isswallowed whole or the capsule is opened and the contents sprinkled onfood prior to eating.

In various embodiments, the particles of the compound of Formula (I),(II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, and one or more excipients are dry blended and compressed intoa mass, such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In still other embodiments, effervescent powders are also prepared.Effervescent salts have been used to disperse medicines in water fororal administration.

In some embodiments, the pharmaceutical solid oral dosage forms areformulated to provide a controlled release of the active compound.Controlled release refers to the release of the active compound from adosage form in which it is incorporated according to a desired profileover an extended period of time. Controlled release profiles include,for example, sustained release, prolonged release, pulsatile release,and delayed release profiles. In contrast to immediate releasecompositions, controlled release compositions allow delivery of an agentto a subject over an extended period of time according to apredetermined profile. Such release rates can provide therapeuticallyeffective levels of agent for an extended period of time and therebyprovide a longer period of pharmacologic response while minimizing sideeffects as compared to conventional rapid release dosage forms. Suchlonger periods of response provide for many inherent benefits that arenot achieved with the corresponding short acting, immediate releasepreparations.

In some embodiments, the solid dosage forms described herein areformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine or large intestine. In one aspect, the enteric coated dosageform is a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. In one aspect, the enteric coated oraldosage form is in the form of a capsule containing pellets, beads orgranules.

Conventional coating techniques such as spray or pan coating areemployed to apply coatings. The coating thickness must be sufficient toensure that the oral dosage form remains intact until the desired siteof topical delivery in the intestinal tract is reached.

In other embodiments, the formulations described herein are deliveredusing a pulsatile dosage form. A pulsatile dosage form is capable ofproviding one or more immediate release pulses at predetermined timepoints after a controlled lag time or at specific sites. Exemplarypulsatile dosage forms and methods of their manufacture are disclosed inU.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329 and 5,837,284.In one embodiment, the pulsatile dosage form includes at least twogroups of particles, (i.e. multiparticulate) each containing theformulation described herein. The first group of particles provides asubstantially immediate dose of the active compound upon ingestion by amammal. The first group of particles can be either uncoated or include acoating and/or sealant. In one aspect, the second group of particlescomprises coated particles. The coating on the second group of particlesprovides a delay of from about 2 hours to about 7 hours followingingestion before release of the second dose. Suitable coatings forpharmaceutical compositions are described herein or in the art.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, and at least onedispersing agent or suspending agent for oral administration to asubject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

In one aspect, liquid formulation dosage forms for oral administrationare in the form of aqueous suspensions selected from the groupincluding, but not limited to, pharmaceutically acceptable aqueous oraldispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g.,Singh et al., Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp.754-757 (2002). In addition to the particles of the compound of Formula(I), the liquid dosage forms include additives, such as: (a)disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) atleast one preservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

Buccal formulations that include a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, areadministered using a variety of formulations known in the art. Forexample, such formulations include, but are not limited to, U.S. Pat.Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136. In addition, thebuccal dosage forms described herein can further include a bioerodible(hydrolysable) polymeric carrier that also serves to adhere the dosageform to the buccal mucosa. For buccal or sublingual administration, thecompositions may take the form of tablets, lozenges, or gels formulatedin a conventional manner.

In some embodiments, compounds of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, are prepared astransdermal dosage forms. In one embodiment, the transdermalformulations described herein include at least three components: (1) aformulation of a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof; (2) a penetrationenhancer; and (3) an aqueous adjuvant. In some embodiments thetransdermal formulations include additional components such as, but notlimited to, gelling agents, creams and ointment bases, and the like. Insome embodiments, the transdermal formulation further includes a wovenor non-woven backing material to enhance absorption and prevent theremoval of the transdermal formulation from the skin. In otherembodiments, the transdermal formulations described herein can maintaina saturated or supersaturated state to promote diffusion into the skin.

In one aspect, formulations suitable for transdermal administration ofcompounds described herein employ transdermal delivery devices andtransdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In one aspect, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. Stillfurther, transdermal delivery of the compounds described herein can beaccomplished by means of iontophoretic patches and the like. In oneaspect, transdermal patches provide controlled delivery of the activecompound. In one aspect, transdermal devices are in the form of abandage comprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In one aspect, a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, is formulated intoa pharmaceutical composition suitable for intramuscular, subcutaneous,or intravenous injection. In one aspect, formulations suitable forintramuscular, subcutaneous, or intravenous injection includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethylene-glycol, glycerol, cremophor and the like), vegetable oilsand organic esters, such as ethyl oleate. In some embodiments,formulations suitable for subcutaneous injection contain additives suchas preserving, wetting, emulsifying, and dispensing agents. Prolongedabsorption of the injectable pharmaceutical form can be brought about bythe use of agents delaying absorption, such as aluminum monostearate andgelatin.

For intravenous injections, compounds described herein are formulated inaqueous solutions, preferably in physiologically compatible buffers suchas Hank's solution, Ringer's solution, or physiological saline buffer.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations include aqueous or nonaqueous solutions, preferably withphysiologically compatible buffers or excipients. Such excipients areknown.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. In one aspect, the active ingredient is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

Methods of Dosing and Treatment Regimens

In one embodiment, the compounds of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, are used in thepreparation of medicaments for the treatment of diseases or conditionsin a mammal that would benefit from a reduction of estrogen receptoractivity. Methods for treating any of the diseases or conditionsdescribed herein in a mammal in need of such treatment, involvesadministration of pharmaceutical compositions that include at least onecompound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, or a pharmaceuticallyacceptable salt, active metabolite, prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidmammal.

In certain embodiments, the compositions containing the compound(s)described herein are administered for prophylactic and/or therapeutictreatments. In certain therapeutic applications, the compositions areadministered to a patient already suffering from a disease or condition,in an amount sufficient to cure or at least partially arrest at leastone of the symptoms of the disease or condition. Amounts effective forthis use depend on the severity and course of the disease or condition,previous therapy, the patient's health status, weight, and response tothe drugs, and the judgment of the treating physician. Therapeuticallyeffective amounts are optionally determined by methods including, butnot limited to, a dose escalation clinical trial.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In one aspect, prophylactic treatments include administeringto a mammal, who previously experienced at least one symptom of thedisease being treated and is currently in remission, a pharmaceuticalcomposition comprising a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, in order toprevent a return of the symptoms of the disease or condition.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of the compounds areadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In certain embodiments wherein a patient's status does improve, the doseof drug being administered may be temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Inspecific embodiments, the length of the drug holiday is between 2 daysand 1 year, including by way of example only, 2 days, 3 days, 4 days, 5days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, ormore than 28 days. The dose reduction during a drug holiday is, by wayof example only, by 10%-100%, including by way of example only 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, and 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, in specificembodiments, the dosage or the frequency of administration, or both, isreduced, as a function of the symptoms, to a level at which the improveddisease, disorder or condition is retained. In certain embodiments,however, the patient requires intermittent treatment on a long-termbasis upon any recurrence of symptoms.

The amount of a given agent that corresponds to such an amount variesdepending upon factors such as the particular compound, diseasecondition and its severity, the identity (e.g., weight, sex) of thesubject or host in need of treatment, but can nevertheless be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated.

In general, however, doses employed for adult human treatment aretypically in the range of 0.01 mg-5000 mg per day. In one aspect, dosesemployed for adult human treatment are from about 1 mg to about 1000 mgper day. In one embodiment, the desired dose is conveniently presentedin a single dose or in divided doses administered simultaneously or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

In one embodiment, the daily dosages appropriate for the compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, described herein are from about 0.01 to about10 mg/kg per body weight. In some embodiments, the daily dosage or theamount of active in the dosage form are lower or higher than the rangesindicated herein, based on a number of variables in regard to anindividual treatment regime. In various embodiments, the daily and unitdosages are altered depending on a number of variables including, butnot limited to, the activity of the compound used, the disease orcondition to be treated, the mode of administration, the requirements ofthe individual subject, the severity of the disease or condition beingtreated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ and the ED₅₀. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD₅₀ and ED₅₀. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the compounds describedherein lies within a range of circulating concentrations that includethe ED₅₀ with minimal toxicity. In certain embodiments, the daily dosagerange and/or the unit dosage amount varies within this range dependingupon the dosage form employed and the route of administration utilized.

Combination Treatments

In certain instances, it is appropriate to administer at least onecompound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, in combination with one ormore other therapeutic agents.

In one embodiment, the therapeutic effectiveness of one of the compoundsdescribed herein is enhanced by administration of an adjuvant (i.e., byitself the adjuvant may have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, in some embodiments, thebenefit experienced by a patient is increased by administering one ofthe compounds described herein with another therapeutic agent (whichalso includes a therapeutic regimen) that also has therapeutic benefit.

In one specific embodiment, a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, isco-administered with a second therapeutic agent, wherein the compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, and the second therapeutic agent modulatedifferent aspects of the disease, disorder or condition being treated,thereby providing a greater overall benefit than administration ofeither therapeutic agent alone.

In any case, regardless of the disease, disorder or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit.

In certain embodiments, different therapeutically-effective dosages ofthe compounds disclosed herein will be utilized in formulatingpharmaceutical composition and/or in treatment regimens when thecompounds disclosed herein are administered in combination with one ormore additional agent, such as an additional therapeutically effectivedrug, an adjuvant or the like. Therapeutically-effective dosages ofdrugs and other agents for use in combination treatment regimens can bedetermined by means similar to those set forth hereinabove for theactives themselves. Furthermore, the methods of prevention/treatmentdescribed herein encompasses the use of metronomic dosing, i.e.,providing more frequent, lower doses in order to minimize toxic sideeffects. In some embodiments, a combination treatment regimenencompasses treatment regimens in which administration of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, is initiated prior to, during, or aftertreatment with a second agent described herein, and continues until anytime during treatment with the second agent or after termination oftreatment with the second agent. It also includes treatments in which acompound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, and the second agent beingused in combination are administered simultaneously or at differenttimes and/or at decreasing or increasing intervals during the treatmentperiod. Combination treatment further includes periodic treatments thatstart and stop at various times to assist with the clinical managementof the patient.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors (e.g. the disease, disorder orcondition from which the subject suffers; the age, weight, sex, diet,and medical condition of the subject). Thus, in some instances, thedosage regimen actually employed varies and, in some embodiments,deviates from the dosage regimens set forth herein.

For combination therapies described herein, dosages of theco-administered compounds vary depending on the type of co-drugemployed, on the specific drug employed, on the disease or conditionbeing treated and so forth. In additional embodiments, whenco-administered with one or more other therapeutic agents, the compoundprovided herein is administered either simultaneously with the one ormore other therapeutic agents, or sequentially.

In combination therapies, the multiple therapeutic agents (one of whichis one of the compounds described herein) are administered in any orderor even simultaneously. If administration is simultaneous, the multipletherapeutic agents are, by way of example only, provided in a single,unified form, or in multiple forms (e.g., as a single pill or as twoseparate pills).

The compounds of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, as well as combinationtherapies, are administered before, during or after the occurrence of adisease or condition, and the timing of administering the compositioncontaining a compound varies. Thus, in one embodiment, the compoundsdescribed herein are used as a prophylactic and are administeredcontinuously to subjects with a propensity to develop conditions ordiseases in order to prevent the occurrence of the disease or condition.In another embodiment, the compounds and compositions are administeredto a subject during or as soon as possible after the onset of thesymptoms. In specific embodiments, a compound described herein isadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease. In some embodiments, the lengthrequired for treatment varies, and the treatment length is adjusted tosuit the specific needs of each subject. For example, in specificembodiments, a compound described herein or a formulation containing thecompound is administered for at least 2 weeks, about 1 month to about 5years.

Exemplary Agent for use in Combination Therapy

In some embodiments, methods for treatment of estrogenreceptor-dependent or estrogen receptor-mediated conditions or diseases,such as proliferative disorders, including cancer, comprisesadministration to a mammal a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, incombination with at least one additional therapeutic agent.

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, in combinationwith hormone blocking therapy, chemotherapy, radiation therapy,monoclonal antibodies, or combinations thereof.

Hormone blocking therapy includes the use of agents that block theproduction of estrogens or block the estrogen receptors. In someembodiments, hormone blocking therapy includes the use of estrogenreceptor modulators and/aromatase inhibitors. Estrogen receptormodulators include triphenylethylene derivatives (e.g. tamoxifen,toremifene, droloxifene, 3-hydroxytamoxifen, idoxifene, TAT-59 (aphosphorylated derivative of 4-hydroxytamoxifen) and GW5638 (acarboxylic acid derivative of tamoxifen)); non-steroidal estrogenreceptor modulators (e.g. raloxifene, LY353381 (SERM3) and LY357489);steroidal estrogen receptor modulators (e.g. ICI-182,780). Aromataseinhibitors include steroidal aromatase inhibitors and non-steroidalaromatase inhibitors. Steroidal aromatase inhibitors include, but arenot limited to, such exemestane. Non-steroidal aromatase inhibitorsinclude, but are not limited to, as anastrozole, and letrozole.

Chemotherapy includes the use of anti-cancer agents.

Monoclonal antibodies include, but are not limited to, trastuzumab(Herceptin).

In some embodiments, the at least one additional therapeutic agent foruse in combination with the compounds of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, include oneor more of the following: abiraterone; abarelix; adriamycin;aactinomycin; acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; alemtuzumab; allopurinol; alitretinoin;altretamine; ambomycin; ametantrone acetate; aminoglutethimide;aminolevulinic acid; amifostine; amsacrine; anastrozole; anthramycin;aprepitant; arsenic trioxide; asparaginase; asperlin; azacitidine;azetepa; azotomycin; batimastat; bendamustine hydrochloride; benzodepa;bevacizumab; bexarotene; bicalutamide; bisantrene hydrochloride;bisnafide dimesylate; bizelesin; bleomycin; bleomycin sulfate;bortezomib; brequinar sodium; bropirimine; busulfan; cactinomycin;calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; capecitabine; cedefingol; cetuximab;chlorambucil; cirolemycin; cisplatin; cladribine; clofarabine; crisnatolmesylate; cyclophosphamide; cytarabine; dacarbazine; dasatinib;daunorubicin hydrochloride; dactinomycin; darbepoetin alfa; decitabine;degarelix; denileukin diftitox; dexormaplatin; dexrazoxanehydrochloride; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel;doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifenecitrate; dromostanolone propionate; duazomycin; edatrexate; eflornithinehydrochloride; elsamitrucin; eltrombopag olamine; enloplatin; enpromate;epipropidine; epirubicin hydrochloride; epoetin alfa; erbulozole;erlotinib hydrochloride; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; everolimus; exemestane; fadrozole hydrochloride;fazarabine; fenretinide; filgrastim; floxuridine; fludarabine phosphate;fluorouracil; fluorocitabine; fosquidone; fostriecin sodium;fulvestrant; gefitinib; gemcitabine; gemcitabine hydrochloride;gemcitabine-cisplatin; gemtuzumab ozogamicin; goserelin acetate;histrelin acetate; hydroxyurea; idarubicin hydrochloride; ifosfamide;iimofosine; ibritumomab tiuxetan; idarubicin; ifosfamide; imatinibmesylate; imiquimod; interleukin II (including recombinant interleukinII, or r1L2), interferon alfa-2a; interferon alfa-2b; interferonalfa-n1; interferon alfa-n3; interferon beta-1a; interferon gamma-1b;iproplatin; irinotecan hydrochloride; ixabepilone; lanreotide acetate;lapatinib; lenalidomide; letrozole; leuprolide acetate; leucovorincalcium; leuprolide acetate; levamisole; liposomal cytarabine; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; methoxsalen; metoprine; meturedepa;mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycinC; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid;nandrolone phenpropionate; nelarabine; nilotinib; nocodazoie;nofetumomab; nogalamycin; ofatumumab; oprelvekin; ormaplatin;oxaliplatin; oxisuran; paclitaxel; palifermin; palonosetronhydrochloride; pamidronate; pegfilgrastim; pemetrexed disodium;pentostatin; panitumumab; pazopanib hydrochloride; pemetrexed disodium;plerixafor; pralatrexate; pegaspargase; peliomycin; pentamustine;peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantronehydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin;prednimustine; procarbazine hydrochloride; puromycin; puromycinhydrochloride; pyrazofurin; quinacrine; raloxifene hydrochloride;rasburicase; recombinant HPV bivalent vaccine; recombinant HPVquadrivalent vaccine; riboprine; rogletimide; rituximab; romidepsin;romiplostim; safingol; safingol hydrochloride; sargramostim; semustine;simtrazene; sipuleucel-T; sorafenib; sparfosate sodium; sparsomycin;spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin;streptozocin; sulofenur; sunitinib malate; talisomycin; tamoxifencitrate; tecogalan sodium; tegafur; teloxantrone hydrochloride;temozolomide; temoporfin; temsirolimus; teniposide; teroxirone;testolactone; thalidomide; thiamiprine; thioguanine; thiotepa;tiazofurin; tirapazamine; topotecan hydrochloride; toremifene;tositumomab and I 131 Iodine tositumomab; trastuzumab; trestoloneacetate; tretinoin; triciribine phosphate; trimetrexate; trimetrexateglucuronate; triptorelin; tubulozole hydrochloride; uracil mustard;uredepa; valrubicin; vapreotide; verteporfin; vinblastine; vinblastinesulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidinesulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbinetartrate; vinrosidine sulfate; vinzolidine sulfate; vorinostat;vorozole; zeniplatin; zinostatin; zoledronic acid; or zorubicinhydrochloride.

In some embodiments, the at least one additional chemotherapeutic agentis selected from, by way of example only, alemtuzumab, arsenic trioxide,asparaginase (pegylated or non-), bevacizumab, cetuximab, platinum-basedcompounds such as cisplatin, cladribine,daunorubicin/doxorubicin/idarubicin, irinotecan, fludarabine,5-fluorouracil, gemtuzumab, methotrexate, taxol, temozolomide,thioguanine, or classes of drugs including hormones (an antiestrogen, anantiandrogen, or gonadotropin releasing hormone analogues, interferonssuch as alpha interferon, nitrogen mustards such as busulfan ormelphalan or mechlorethamine, retinoids such as tretinoin, topoisomeraseinhibitors such as irinotecan or topotecan, tyrosine kinase inhibitorssuch as gefinitinib or imatinib, or agents to treat signs or symptomsinduced by such therapy including allopurinol, filgrastim,granisetron/ondansetron/palonosetron, dronabinol.

In one aspect, the compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, is administered orformulated in combination with one or more anti-cancer agents. In someembodiments, one or more of the anti-cancer agents are proapoptoticagents. Examples of anti-cancer agents include, but are not limited to,any of the following: gossypol, genasense, polyphenol E, Chlorofusin,all trans-retinoic acid (ATRA), bryostatin, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL),5-aza-2′-deoxycytidine, all trans retinoic acid, doxorubicin,vincristine, etoposide, gemcitabine, imatinib, geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,paclitaxel, and analogs of paclitaxel. Compounds that have the basictaxane skeleton as a common structure feature, have also been shown tohave the ability to arrest cells in the G2-M phases due to stabilizedmicrotubules and may be useful for treating cancer in combination withthe compounds described herein.

Further examples of anti-cancer agents for use in combination with thecompounds of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, include inhibitors ofmitogen-activated protein kinase signaling, e.g., U0126, PD98059,PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006,wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies(e.g., rituxan).

Further examples of anti-cancer agents for use in combination with thecompounds of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, include aromatase inhibitors.Aromatase inhibitors include steroidal aromatase inhibitors andnon-steroidal aromatase inhibitors. Steroidal aromatase inhibitorsinclude, but are not limited to, exemestane. Non-steroidal aromataseinhibitors include, but are not limited to, anastrozole, and letrozole.

Yet other anticancer agents for use in combination with the compounds ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products for use in combination with the compoundsof Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, include but are not limited to vinca alkaloids(e.g., vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents for use in combination with the compoundsof Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.).

In some embodiments, compounds of F Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, are used totreat cancer in combination with: a second antiestrogen (e.g.,tamoxifen), an antiandrogen (e.g., bicalutamide, flutamide), agonadotropin releasing hormone analog (e.g., leuprolide).

Other agents that can be used in the methods and compositions describedherein for the treatment or prevention of cancer include platinumcoordination complexes (e.g., cisplatin, carboblatin), anthracenedione(e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methylhydrazine derivative (e.g., procarbazine), adrenocortical suppressant(e.g., mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules include without limitation thefollowing marketed drugs and drugs in development: Erbulozole,Dolastatin 10, Mivobulin isethionate, Vincristine, NSC-639829,Discodermolide, ABT-751, Altorhyrtins (such as Altorhyrtin A andAltorhyrtin C), Spongistatins (such as Spongistatin 1, Spongistatin 2,Spongistatin 3, Spongistatin 4, Spongistatin 5, Spongistatin 6,Spongistatin 7, Spongistatin 8, and Spongistatin 9), Cemadotinhydrochloride, Epothilones (such as Epothilone A, Epothilone B,Epothilone C, Epothilone D, Epothilone E, Epothilone F, Epothilone BN-oxide, Epothilone A N-oxide, 16-aza-epothilone B, 21-aminoepothiloneB, 21-hydroxyepothilone D, 26-fluoroepothilone, Auristatin PE,Soblidotin, Vincristine sulfate, Cryptophycin 52, Vitilevuamide,Tubulysin A, Canadensol, Centaureidin, Oncocidin A1 Fijianolide B,Laulimalide, Narcosine, Nascapine, Hemiasterlin, Vanadoceneacetylacetonate, Indanocine Eleutherobins (such asDesmethyleleutherobin, Desaetyleleutherobin, lsoeleutherobin A, andZ-Eleutherobin), Caribaeoside, Caribaeolin, Halichondrin B, DiazonamideA, Taccalonolide A, Diozostatin, (−)-Phenylahistin, Myoseverin B,Resverastatin phosphate sodium.

In one aspect, a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, is co-administeredwith thrombolytic agents (e.g., alteplase anistreplase, streptokinase,urokinase, or tissue plasminogen activator), heparin, tinzaparin,warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors(e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban,LY517717, or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel,LY640315), ximelagatran, or BIBR 1048.

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, is used incombination with anti-emetic agents to treat nausea or emesis, which mayresult from the use of a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, anti-canceragent(s) and/or radiation therapy.

Anti-emetic agents include, but are not limited to: neurokinin-1receptor antagonists, 5HT3 receptor antagonists (such as ondansetron,granisetron, tropisetron, palonosetron, and zatisetron), GABA_(B)receptor agonists (such as baclofen), corticosteroids (such asdexamethasone, prednisone, prednisolone, or others), dopamineantagonists (such as, but not limited to, domperidone, droperidol,haloperidol, chlorpromazine, promethazine, prochlorperazine,metoclopramide), antihistamines (H1 histamine receptor antagonists, suchas but not limited to, cyclizine, diphenhydramine, dimenhydrinate,meclizine, promethazine, hydroxyzine), cannabinoids (such as but notlimited to, cannabis, marinol, dronabinol), and others (such as, but notlimited to, trimethobenzamide; ginger, emetrol, propofol).

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, is used incombination with an agent useful in the treatment of anemia. Such ananemia treatment agent is, for example, a continuous eythropoiesisreceptor activator (such as epoetin-α).

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, is used incombination with an agent useful in the treatment of neutropenia.Examples of agents useful in the treatment of neutropenia include, butare not limited to, a hematopoietic growth factor which regulates theproduction and function of neutrophils such as a human granulocytecolony stimulating factor, (G-CSF). Examples of a G-CSF includefilgrastim.

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, is administeredwith corticosteroids. Corticosteroids, include, but are not limited to:betamethasone, prednisone, alclometasone, aldosterone, amcinonide,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,clobetasone, clocortolone, cloprednol, cortisone, cortivazol,deflazacort, deoxycorticosterone, desonide, desoximetasone,desoxycortone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluprednidene,fluticasone, formocortal, halcinonide, halometasone,hydrocortisone/cortisol, hydrocortisone aceponate, hydrocortisonebuteprate, hydrocortisone butyrate, loteprednol, medrysone,meprednisone, methylprednisolone, methylprednisolone aceponate,mometasone furoate, paramethasone, prednicarbate,prednisone/prednisolone, rimexolone, tixocortol, triamcinolone, andulobetasol.

In one embodiment, a compound of Formula (I), (II), (III), (IV), (V), or(VI), or a pharmaceutically acceptable salt thereof, is administered toa mammal in combination with a non-steroidal anti-inflammatory drug(NSAID). NSAIDs include, but are not limited to: aspirin, salicylicacid, gentisic acid, choline magnesium salicylate, choline salicylate,choline magnesium salicylate, choline salicylate, magnesium salicylate,sodium salicylate, diflunisal, carprofen, fenoprofen, fenoprofencalcium, fluorobiprofen, ibuprofen, ketoprofen, nabutone, ketolorac,ketorolac tromethamine, naproxen, oxaprozin, diclofenac, etodolac,indomethacin, sulindac, tolmetin, meclofenamate, meclofenamate sodium,mefenamic acid, piroxicam, meloxicam, COX-2 specific inhibitors (suchas, but not limited to, celecoxib, rofecoxib, valdecoxib, parecoxib,etoricoxib, lumiracoxib, CS-502, JTE-522, L-745,337 and NS398).

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, iscoadministered with an analgesic.

In some embodiments, a compound of Formula (I), (II), (III), (IV), (V),or (VI), or a pharmaceutically acceptable salt thereof, is used incombination with radiation therapy (or radiotherapy). Radiation therapyis the treatment of cancer and other diseases with ionizing radiation.Radiation therapy can be used to treat localized solid tumors, such ascancers of the skin, tongue, larynx, brain, breast, prostate, colon,uterus and/or cervix. It can also be used to treat leukemia and lymphoma(cancers of the blood-forming cells and lymphatic system, respectively).

A technique for delivering radiation to cancer cells is to placeradioactive implants directly in a tumor or body cavity. This is calledinternal radiotherapy (brachytherapy, interstitial irradiation, andintracavitary irradiation are types of internal radiotherapy.) Usinginternal radiotherapy, the radiation dose is concentrated in a smallarea, and the patient stays in the hospital for a few days. Internalradiotherapy is frequently used for cancers of the tongue, uterus,prostate, colon, and cervix.

The term “radiotherapy” or “ionizing radiation” include all forms ofradiation, including but not limited to α, β, and γ radiation andultraviolet light.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers are formed fromany acceptable material including, e.g., glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically comprise one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

EXAMPLES

These examples are provided for illustrative purposes only and not tolimit the scope of the claims provided herein.

Intermediate 1 N,2,5-Trimethoxy-N-methylbenzamide

Oxalyl chloride (3.6 mL, 41.3 mmol) was added to a solution of2,5-dimethoxybenzoic acid (6.00 g, 33.0 mmol) in DCM (100 mL) at roomtemperature. Then, DMF (0.2 mL) was added to the mixture. The resultingsolution was stirred at room temperature for 2 h, and the solvent wasremoved on a rotary evaporator. The crude material was placed undervacuum for 30 minutes to remove the residual oxalyl chloride to give thecrude acid chloride. Crude material was dissolved in DCM (100 mL) andcooled down to 0° C. To this solution, N,O-dimethylhydroxylaminehydrochloride (4.03 g, 41.32 mmol) and triethylamine (6.8 mL, 48.78mmol) were added respectively. The resulting mixture was stirred at 0°C. for 30 min and then at room temperature for additional 30 min. Thereaction was diluted with DCM (50 mL), washed with H₂O (2×100 mL),washed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated on a rotary evaporator. The crude material was purified bysilica gel chromatography to yield N,2,5-trimethoxy-N-methylbenzamide(7.32 g, 99%) as clear oil which solidified over time. ¹H NMR (CDCl₃): δ7.90 (m, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.58 (br s, 3H), 3.32 (br s,3H).

Intermediate 21-(2-Hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone

Step 1: 1-(2,5-Dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone

A 5 mL portion of 3-methoxybenzyl chloride (12.8 mL, 88.1 mmol) in THF(60 mL) was added to a mixture of magnesium (2.88 g, 118 mmol) andiodine (1 crystal) in THF (30 mL). The reaction mixture was stirreduntil the color disappeared and the remaining solution of3-methoxybenzyl chloride was added dropwise over 45 min. The mixture washeated at 60° C. for 1 h and then cooled to 0° C. A solution ofIntermediate 1 (6.65 g 29.6 mmol) in THF (70 mL) was added to thismixture over 30 min at 0° C. The reaction was stirred for 30 min at 0°C. and quenched with brine (50 mL). The mixture was extracted with ethylacetate (3×100 mL). The combined organic extracts were washed with brine(50 mL), dried over Na₂SO₄, filtered, and concentrated on a rotaryevaporator to give 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone(7.99 g, 95%) as a white solid. ¹H NMR (CDCl₃): δ 7.25 (m, 2H), 7.01(dd, 1H), 6.92 (d, 1H), 6.83 (m, 3H), 4.30 (s, 2H), 3.90 (s, 3H), 3.82(s, 3H), 3.79 (s, 3H).

Step 2: 1-(2,5-Dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone

To a solution of 1-(2,5-dimethoxyphenyl)-2-(3-methoxyphenyl)ethanone(3.35 g, 11.7 mmol) in DCM (50 mL) at −78° C., boron tribromide (1M inDCM, 48.0 mL, 48.0 mmol) was added dropwise. The reaction mixture waswarmed to 0° C., stirred for 30 min, re-cooled to −78° C., and thenquenched with methanol (15 mL). The reaction mixture was warmed to roomtemperature, concentrated on a rotary evaporator and purified by silicagel chromatography to give1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (1.78 g, 62%) as ayellow solid. ¹H NMR (DMSO-d₆): δ 11.24 (s, 1H), 9.34 (s, 1H), 9.20 (s,1H), 7.26 (m, 1H), 7.10 (t, 1H), 6.98 (dd, 1H), 6.83 (d, 1H), 6.70 (m,3H), 4.24 (s, 2H).

Step 3:1-(2-Hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone

3,4-Dihydro-2H-pyran (2.65 g, 30.8 mmol) in DCM (6 mL) was added to amixture of 1-(2,5-dihydroxyphenyl)-2-(3-hydroxyphenyl)ethanone (1.50 g,6.15 mmol) and pyridinium p-toluene sulfonate (320 mg, 1.27 mmol) in DCM(40 mL). The reaction mixture was stirred at room temperature for 1 hand diluted with DCM (100 mL). The solution was washed with sat'd NaHCO₃(2×50 mL), washed with brine (50 mL), dried over Na₂SO₄, filtered, andconcentrated on a rotary evaporator. The crude material was purified bysilica gel chromatography to give1-(2-hydroxy-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)ethanone(2.42 g, 96%) as yellow oil which solidified over time. ¹H NMR (CDCl₃):δ 11.88 (s, 1H), 7.60 (m, 1H), 7.30 (m, 2H), 7.00 (m, 2H), 6.92 (m, 2H),5.42 (m, 1H), 5.28 (m, 1H), 4.25 (s, 2H), 3.92 (m, 2H), 3.62 (m, 2H),1.55-2.07 (m, 12H).

Intermediate 32-(4-Iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene

Step 1:2-(4-Iodophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one

A solution of Intermediate 2 (2.41 g, 5.84 mmol), 4-iodobenzaldehyde(1.37 g, 5.91 mmol), piperidine (166 mg, 1.95 mmol), and DBU (301 mg,1.98 mmol) in s-butanol (10 mL) was heated at reflux. Using a Dean-Starktrap, half (5 mL) of the solvent was collected over 45 min, and thereaction was kept at reflux without further concentration for additional45 min. The reaction mixture was cooled to 90° C., i-propanol (10 mL)was added, and the reaction was allowed to cool to room temperature andstirred overnight. The resulting precipitate was collected by filtrationto yield2-(4-iodophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one(3.17 g, 87%) as a white solid. ¹H NMR (DMSO-d₆): δ 7.63 (d, 2H), 7.42(m, 1H), 7.33 (m, 1H), 7.21 (d, 2H), 7.07 (m, 2H), 6.79 (m, 3H), 5.88(m, 1H), 5.48 (m, 1H), 5.31 (m, 1H), 4.60 (d, 1H), 3.40-3.80 (m, 4H),1.55-1.90 (m, 12H).

Step 2: 3-(3-Hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-6-ol

Methyl magnesium chloride (3M in THF, 4.0 mL, 12 mmol) was addeddropwise to a solution of2-(4-iodophenyl)-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)chroman-4-one(1.99 g, 3.18 mmol) in THF (40 mL) at 0° C. The reaction was stirred at0° C. for 15 min and allowed to warm to room temperature. After stirringfor 2 h, the solution was cooled to 0° C., quenched with sat'd ammoniumchloride, and then allowed to warm to room temperature. Ethyl acetate(100 mL) and H₂O (50 mL) were added, and the layers were separated. Theorganic layer was dried over Na₂SO₄, concentrated on a rotaryevaporator, and purified by silica gel chromatography to yield a whitefoam (1.75 g). This purified material was heated in 80% acetic acid/H₂O(50 mL) overnight at 90° C. The solution was diluted with ethyl acetate(100 mL), washed with H₂O (50 mL), washed with sat'd NaHCO₃ (50 mL),washed with brine (50 mL), and dried over Na₂SO₄, filtered, andconcentrated on a rotary evaporator. The crude material was purified bysilica gel chromatography to give3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-6-ol (0.99 g,68%) as a beige solid. ¹H NMR (DMSO-d₆): δ 9.46 (s, 1H), 9.00 (s, 1H),7.62 (d, 2H), 7.17 (t, 1H), 7.01 (d, 2H), 6.70 (m, 4H), 6.51 (s, 2H),5.90 (s, 1H), 2.03 (s, 3H).

Step 3:2-(4-Iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene

3,4-Dihydro-2H-pyran (1.1 mL, 12 mmol) was added to a solution of3-(3-hydroxyphenyl)-2-(4-iodophenyl)-4-methyl-2H-chromen-6-ol (990 mg,2.19 mmol) and pyridinium p-toluene sulfonate (115 mg, 0.458 mmol) inDCM (30 mL). The reaction was stirred at room temperature for 3 h,diluted with DCM (100 mL), washed with sat'd NaHCO₃ (100 mL), washedwith H₂O (2×50 mL), washed with brine (50 mL), dried over Na₂SO₄,filtered, and concentrated on a rotary evaporator. The crude materialwas purified by silica gel chromatography to give2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene(1.30 g, 95%) as a white foam. ¹H NMR (DMSO-d₆): δ7.62 (d, 2H), 7.27 (t,1H), 7.10 (d, 2H), 6.92 (m, 4H), 6.81 (d, 1H), 6.63 (d, 1H), 6.04 (d,1H), 5.43 (m, 1H), 5.36 (s, 1H), 3.75 (m, 2H), 3.55 (m, 2H), 2.05 (s,3H), 1.50-1.99 (m, 12H).

Intermediate 42-(4-(4-Methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol

A mixture of2-(4-iodophenyl)-4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromene(Intermediate 3, 1.0 g, 1.6 mmol), ethane-1,2-diol (0.49 g, 8.0 mmol),copper iodide (0.03 g, 0.16 mmol), 1,10-phenanthroline (0.058 g, 0.32mmol), potassium carbonate (0.44 g, 3.2 mmol) in butyronitrile (3.2 mL)was degassed three times via nitrogen/vacuum cycles. The reactionmixture was heated at 125° C. for 2 days, allowed to cool to roomtemperature, and diluted with ethyl acetate. This mixture was filteredthrough Celite. The organic phase was washed twice with water, washedwith brine, dried over Na₂SO₄, filtered, and concentrated to afford thecrude product. This crude product was then purified by silica gelchromatography to give2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol.¹H NMR (DMSO-d₆): δ 7.27-7.13 (m, 3H), 6.98 (t, 1H), 6.93-6.84 (m, 3H),6.80-6.76 (m, 3H), 6.59 (d, 1H), 5.97 (d, 1H), 5.43 (dt, 1H), 5.34 (br,1H), 4.79 (t, 1H), 3.88 (t, 2H), 3.80-3.70 (m, 2H), 3.64 (q, 2H),3.54-3.50 (m, 2H), 2.06 (s, 3H), 1.86-1.66 (m, 6H), 1.59-1.51 (m, 6H).

Intermediate 52-(4-(4-Methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethylmethanesulfonate

To a solution of2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethanol(Intermediate 4, 0.7 g, 1.25 mmol) in DCM (25 mL) at 0° C.,triethylamine (0.26 mL, 1.87 mmol) and methanesulfonyl chloride (0.146mL, 1.87 mmol) were added respectively. The reaction mixture was stirredat 0° C. for 1 h, and then diluted with DCM. To this mixture, water (20mL), and sat'd ammonium chloride (20 mL) were added. The layers wereseparated and the organic layer was washed with water, washed withsaturated NaHCO₃, washed with brine, dried over Na₂SO₄, and concentratedto give2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethylmethanesulfonate (0.7 g). ¹H NMR (DMSO-d₆): δ 7.25 (d, 3H), 6.99-6.98(m, 1H), 6.93-6.87 (m, 3H), 6.85-6.78 (m, 2H), 6.77-6.75 (dd, 1H), 6.61(d, 1H), 5.98 (d, 1H), 5.43 (d, 1H), 5.34 (br, 1H), 4.47-4.45 (m, 2H),4.16 (br, 2H), 3.83-3.70 (m, 2H), 3.56-3.47 (m, 2H), 3.18 (s, 3H), 2.05(s, 3H), 1.92-1.65 (m, 6H), 1.60-1.40 (m, 6H).

Intermediate 6 3-(Fluoromethyl)azetidine 2,2,2-trifluoroacetate

Step 1: tert-Butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(8.8 g, 47 mmol) in DCM (188 mL) at 0° C., triethylamine (7.8 mL, 56mmol) was added in one portion. Then, neat methanesulfonyl chloride(4.38 mL, 56 mmol) was added via an additional funnel over 30 minutes.The resulting mixture was stirred at 0° C. for 1.5 h. Upon completion ofthe reaction, water (100 mL) and sat'd aqueous ammonium chloride (100mL) were added respectively. The organic phase was separated and washedtwice with water, washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford the crude tert-butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate as a pale yellowoil (12.5 g). This compound was used directly for the next step withoutfurther purification.

Step 2: tert-Butyl 3-(fluoromethyl)azetidine-1-carboxylate

A mixture of tert-butyl3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (12.5 g, 47 mmol)and 235 mL tetrabutylammonium fluoride (1M solution in THF, 5 equiv.)was heated at reflux for 18 h. The reaction mixture was cooled to roomtemperature and excess THF was removed on a rotary evaporator. Theresidue was dissolved in ethyl acetate. The organic phase was washedwith sat'd aqueous NaHCO₃, washed with water, washed with brine, driedover Na₂SO₄, filtered and concentrated on a rotary evaporator to givethe crude product. This crude product was purified by silica gelchromatography to afford tert-butyl3-(fluoromethyl)azetidine-1-carboxylate as clear oil (7.5 g). ¹H NMR(DMSO-d₆): δ 4.52 (dd, 2H), 3.89 (br, 2H), 3.61 (br, 2H), 2.92-2.77 (m,1H), 1.36 (s, 9H).

Step 3: 3-(Fluoromethyl)azetidine 2,2,2-trifluoroacetate

tert-Butyl 3-(fluoromethyl)azetidine-1-carboxylate (0.1 g, 0.53 mmol)and trifluoroacetic acid/DCM (1:1, 5.3 mL) was stir at room temperaturefor 30 min. Then the reaction mixture was concentrated on a rotaryevaporator to afford 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate asclear oil. ¹H NMR (DMSO-d₆; TFA salt): δ 8.74 (br, 2H), 4.54 (dd, 2H),4.08-3.98 (m, 2H), 3.84-3.76 (m, 2H), 3.20-3.06 (m, 1H).

Intermediate 7 2-(3-(Fluoromethyl)azetidin-1-yl)ethanol

A mixture of 3-(fluoromethyl)azetidine 2,2,2-trifluoroacetate(Intermediate 6, 100 mg, 0.5 mmol), 2-bromoethanol (60 mg, 0.5 mmol),and potassium carbonate (0.2 g, 1.5 mmol) in acetonitrile (5 mL) washeated to 80° C. overnight. After cooling, solids were filtered off andwashed with acetonitrile. The filtrate was concentrated on a rotaryevaporator to give a residue that was purified by silica gelchromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethylacetate/hexane/methanol/triethylamine to afford 52 mg of2-(3-(fluoromethyl)azetidin-1-yl)ethanol as a pale yellow oil. ¹H NMR(DMSO-d₆): δ 5.13 (t, 1H), 4.62 (d, 1H), 4.50 (d, 1H), 4.06 (t, 2H),3.84 (dd, 2H), 3.54 (q, 2H), 3.11 (t, 2H), 3.06-3.03 (m, 1H).

Intermediate 8 (R)-3-(Fluoromethyl)pyrrolidine hydrochloride

Step 1: (R)-tert-Butyl3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate

A mixture of (R)-tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate(21.5 g, 107 mmol) and triethylamine (30 mL, 214 mmol) indichloromethane (250 mL) was cooled to 0° C. Methanesulfonyl chloride(12.5 mL, 160.5 mmol) was added dropwise via an addition funnel and theresulting mixture was stirred at 0° C. then gradually warmed to roomtemperature over 3 h. A 10% aqueous citric acid solution was added andthe two layers were separated. The organic layer was washed with 10%aqueous citric acid, sat'd aqueous NaHCO₃, and brine. The organic layerwas dried over sodium sulfate, filtered and the solvent removed on arotary evaporator to afford 30 g of (R)-tert-butyl3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate as an orangeoil that was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 4.17 (m, 2H), 3.33 (m, 2H), 3.20 (m, 1H), 3.18 (s, 3H), 3.00(m, 1H), 2.55 (m, 1H), 2.01 (m, 1H), 1.53 (m, 1H), 1.40 (s, 9H).

Step 2: (R)-tert-Butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate

Tetrabutylammonium fluoride (1M solution in THF, 530 mL) was added to(R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate(30 g from previous step) and the resulting mixture was refluxedovernight. After cooling, the solvent was removed and the residue waspartitioned between 10% aqueous citric acid and dichloromethane. Theorganic layer was washed with water, dried over sodium sulfate, filteredand the solvent was removed on a rotary evaporator. The residue waspurified by flash chromatography on a silica gel column (0 to 50% ethylacetate/hexanes) to afford 14.3 g of (R)-tert-butyl3-(fluoromethyl)pyrrolidine-1-carboxylate as a yellow oil. ¹H NMR (400MHz, DMSO-d₆) δ 4.49-4.41 (m, 1H), 4.37-4.29 (m, 1H), 3.40-3.28 (m, 2H),3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.58-2.52 (m, 1H), 1.95-1.88 (m,1H), 1.67-1.54 (m, 1H), 1.38 (s, 9H).

Step 3: (R)-3-(Fluoromethyl)pyrrolidine hydrochloride

(R)-tert-Butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate (14.3 g, 70.4mmol) in 1,4-dioxane (60 mL) was cooled in an ice bath HCl (4M in1,4-dioxane, 44 mL, 176 mmol) was then added and the resulting pinksolution was stirred at room temperature overnight. The solvent wasremoved on a rotary evaporator and the residue was triturated withdiethyl ether. Diethyl ether was removed under vacuum and the pink solidwas dried to afford 9.5 g of (R)-3-(fluoromethyl)pyrrolidinehydrochloride. ¹H NMR (400 MHz, DMSO-d₆; HCl salt) δ 9.35 (bs, 2H),4.57-4.47 (m, 1H), 4.44-4.33 (m, 1H), 3.33-3.10 (m, 3H), 2.95-2.87 (m,1H), 2.69-2.57 (m, 1H), 2.005-1.97 (m, 1H), 1.70-1.61 (m, 1H).

Intermediates in Table 2 were prepared from commercially availableamines following the general procedures described for Intermediate 8.

TABLE 2 Intermediate Structure Name and ¹H NMR Data 9

(S)-2-(fluoromethyl)pyrrolidine hydrochloride: ¹H NMR (DMSO-d₆; HClsalt): δ 9.52 (br, 1H), 9.15 (br, 1H), 4.77-4.22 (m, 2H), 3.88-3.73 (m,1H), 3.17 (t, 2H), 2.08-1.98 (m, 1H), 1.98-1.82 (m, 2H), 1.67-1.59 (m,1H). 10

4-(Fluoromethyl)piperidine hydrochloride : ¹H NMR (DMSO- d₆; HCl salt):δ 9.22 (br, 1H), 8.90 (br, 1H), 4.30 (dd, 2H), 3.27- 3.18 (m, 2H),2.90-2.77 (m, 2H), 2.03-1.87 (m, 1H), 1.81-1.72 (m, 2H), 1.52-1.39 (m,2H). 11

(R)-3-(fluoromethyl)piperidine hydrochloride: ¹H NMR (DMSO-d₆: HClsalt): δ 9.11 (br, 2H), 4.49-4.24 (m, 2H), 3.21 (t, 2H), 2.80-2.62 (m,2H), 2.22-2.07 (m, 1H), 1.82-1.63 (m, 3H), 1.32-1.21 (m, 1H).

Intermediate 12 (R)-3-(Difluoromethyl)pyrrolidine hydrochloride

Step 1: (R)-tert-Butyl 3-formylpyrrolidine-1-carboxylate

DMSO (1.4 mL, 19.69 mmol) in dichloromethane (2 mL) was added dropwiseto a solution of oxalyl chloride (0.86 mL, 9.85 mmol) in dichloromethane(10 mL) at −78° C. After 10 min at −78° C., (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate (1.8 g, 8.95 mmol) indichloromethane (6 mL) was added dropwise. After the resulting mixturewas stirred at −78° C. for 30 min, triethylamine (6.2 mL, 44.75 mmol)was added and the mixture was stirred at −78° C. for 45 min then at roomtemperature for 30 min. Water was added to the reaction mixture and thetwo layers were separated. The organic layer was washed with water,dried over sodium sulfate, filtered and the solvent removed. The crudematerial was purified by flash chromatography on silica gel eluting with0 to 50% ethyl acetate/hexanes to afford 0.6 g of (R)-tert-butyl3-formylpyrrolidine-1-carboxylate as a clear oil. ¹H NMR (400 MHz,DMSO-d₆) δ 9.60 (s, 1H), 3.54 (dd, 1H), 3.32-3.21 (m, 2H), 3.12 (m, 2H),2.04 (m, 2H), 1.39 (s, 9H).

Step 2: (R)-tert-Butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate

(R)-tert-Butyl 3-formylpyrrolidine-1-carboxylate (0.6 g, 3.06 mmol) indichloromethane (5 mL) was cooled to 0° C. Diethylaminosulfurtrifluoride (DAST, 0.52 mL, 3.98 mmol) was added dropwise and theresulting mixture was stirred at room temperature overnight. Water wasadded to the reaction mixture and the two layers were separated. Theorganic layer was washed with sat'd aqueous NaHCO₃, dried over sodiumsulfate, filtered and the filtrate was concentrated on a rotaryevaporator. The crude material was purified by flash chromatography onsilica gel eluting with 0 to 50% ethyl acetate/hexanes to afford 0.45 gof (R)-tert-butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate as a clearoil. ¹H NMR (400 MHz, DMSO-d₆) δ 6.08 (td, 1H), 3.34 (m, 2H), 3.19 (m,2H), 2.70 (m, 1H), 1.95 (m, 1H), 1.82 (m, 1H), 1.39 (s, 9H).

Step 3: (R)-3-(Difluoromethyl)pyrrolidine hydrochloride

(R)-tert-Butyl 3-(difluoromethyl)pyrrolidine-1-carboxylate (0.45 g, 2.03mmol) in 1,4-dioxane (1 mL) was cooled to 15° C. in an ice bath. HCl (4Min 1,4-dioxane, 1.5 mL, 6.11 mmol) was then added and the resultingsolution was stirred at room temperature overnight. The solvent wasremoved on a rotary evaporator and the residue was triturated withdiethyl ether. Diethyl ether was removed under vacuum and solid wasdried to afford 0.31 g of (R)-3-(difluoromethyl)pyrrolidinehydrochloride as a grey solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (bs,2H), 6.19 (td, 1H), 3.34 (m, 1H), 3.22-3.06 (m, 3H), 2.82 (m, 1H), 2.05(m, 1H), 1.85 (m, 1H).

Intermediate 13 (R)-2-(3-(Fluoromethyl)pyrrolidin-1-yl)ethanol

A mixture of (R)-3-(fluoromethyl)pyrrolidine hydrochloride (Intermediate8, 4.26 g, 30.6 mmol), 2-bromoethanol (4.35 mL, 61.3 mmol), andpotassium carbonate (12.7 g, 92 mmol) in acetonitrile (120 mL) washeated at 80° C. overnight. After cooling, solids were filtered off andwashed with acetonitrile. The filtrate was concentrated on a rotaryevaporator to give a residue that was purified by silica gelchromatography eluting with 10:7 ethyl acetate/hexanes to 10:7:2:1 ethylacetate/hexane/methanol/triethylamine to afford 2.9 g of(R)-2-(3-(fluoromethyl)pyrrolidin-1-yl)ethanol as a clear oil. ¹H NMR(400 MHz, DMSO-d₆) δ 4.44 (t, 1H), 4.34 (dd, 1H), 4.22 (dd, 1H), 3.44(q, 2H), 2.58-2.51 (m, 1H), 2.48-2.38 (m, 5H), 2.32-2.28 (m, 1H),1.85-1.74 (m, 1H), 1.39-1.31 (m, 1H).

Intermediate 14 (S)-2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)propan-1-ol

Step 1: (R)-1-(Trityloxy)propan-2-ol

Dimethylaminopyridine (165 mg, 1.35 mmol) was added to a solution of(R)-propane-1,2-diol (10.3 g, 135.4 mmol) and trityl chloride (38.1 g136.7 mmol) in DCM (400 mL) at 0° C. Triethylamine (47.2 mL, 338.4 mmol)was then added dropwise to this mixture. The solution was allowed towarm to room temperature and stirred overnight. The reaction mixture waswashed with 1.0 N aq HCl (200 mL), washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by silica gel chromatography to give(R)-1-(trityloxy)propan-2-ol (36.4 g, 84%) as a white solid. ¹H NMR (400MHz, DMSO-d₆): δ 7.43-7.39 (m, 6H) 7.34-7.31 (m, 6H) 7.26-7.22 (m, 3H),4.70 (d, 1H), 3.82-3.76 (m, 1H), 2.95-2.92 (dd, 1H), 2.70-2.67 (dd, 1H),1.06 (d, 3H).

Step 2: (R)-3-(Fluoromethyl)-1-(S)-1-(trityloxy)propan-2-yl)pyrrolidine

Triflic anhydride (1.0 M in DCM, 51.8 mL, 51.8 mmol) was added dropwiseto a solution of (R)-1-(trityloxy)propan-2-ol (15.0 g, 47.1 mmol) anddiisopropylethylamine (32.8 mL, 188.4 mmol) in DCM (190 mL) at −78° C.The reaction mixture was allowed to stir at −78° C. for 1.5 h.(R)-3-(Fluoromethyl)pyrrolidine hydrochloride (Intermediate 8, 7.9 g,56.5 mmol) in DCM (20 mL) was added dropwise to the reaction mixture at−78° C. The mixture was allowed to warm to room temperature and stirredat this temperature overnight. Water (200 mL) and sat'd aqueous NaHCO₃(200 mL) was added to the mixture. The mixture was poured into aseparatory funnel and the layers were separated. The aqueous layer waswashed twice with DCM. The organic layers were combined, dried overNa₂SO₄, filtered, and concentrated on a rotary evaporator to afford thecrude material that was used directly for the next step without furtherpurification.

Step 3: (S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-1-ol

A mixture of(R)-3-(fluoromethyl)-1-((S)-1-(trityloxy)propan-2-yl)pyrrolidine (19.0g, 47.1 mmol) and formic acid/diethyl ether (4:1, 189 mL) was stirred atroom temperature for 8 h. This reaction mixture was concentrated on arotary evaporator. The residue was dissolved in DCM, washed with sat'daqueous K₂CO₃, and washed with brine. Organic layer was dried overNa₂SO₄, filtered, and concentrated to give the crude product that waspurified by silica gel chromatography (10:7 ethyl acetate/hexanes to10:7:2:1 ethyl acetate/hexane/methanol/triethylamine) to afford(S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propan-1-ol (3.9 g) as a darkorange oil. ¹H NMR (400 MHz, DMSO-d₆) δ 4.38-4.32 (m, 2H), 4.22-4.20 (m,1H), 3.49-3.44 (m, 1H), 3.21-3.16 (m, 1H), 2.65-2.61 (m, 1H), 2.58-2.53(m, 1H), 2.52-2.47 (m, 1H), 2.45-2.35 (m, 1H), 2.34-2.30 (m, 1H),2.29-2.24 (m, 1H), 1.83-1.75 (m, 1H), 1.38-1.30 (m, 1H), 0.98 (d, 3H).

General Procedure A Friedel-Crafts Acylation

A mixture of 1.8 equivalents of a 1-methoxybenzene (for example1,4-dimethoxybenzene), the appropriate phenylacetic acid (1.0 equiv) andpolyphosphoric acid (1.3-1.5 M) was heated at 75° C. for 5-24 h andcooled to 50° C. Water (1-2 fold of PPA v/v) was added, and the mixturewas allowed to cool to room temperature. Additional water (1-2 fold PPAv/v) was added and the mixture was extracted with DCM (or ether). Theorganic phase was washed with H₂O, washed with brine, dried over Na₂SO₄(or MgSO₄), filtered, and concentrated to afford the crude product. Thiscrude product was then purified by silica gel chromatography to give thecorresponding alkoxyaryl ketone.

General Procedure B Step 1: Synthesis of Weinreb Amide

Oxalyl chloride (1.25 equiv) was added to a solution of a 1.0equivalents of a 2-alkoxybenzoic acid (for example 2,5-dimethoxybenzoicacid) in DCM (0.33 M). Then DMF (5% v/v of oxalyl chloride) was added tothe mixture. The solution was stirred at room temperature for 2 h andthe solvent was removed under reduced pressure. The crude material wasplaced under vacuum for 30 min to remove the residual oxalyl chloride.Triethylamine (1.2 equiv) was added dropwise to a solution of theresidue and N,O-dimethylhydroxylamine hydrochloride (1.0 equiv) in DCM(0.33 M) at 0° C. The solution was stirred at 0° C. for 30 min and thenat room temperature for additional 30 min. The reaction was diluted withDCM, washed twice with water, washed with brine, dried over Na₂SO₄ (orMgSO₄), filtered, and concentrated to afford the crude product. Thiscrude product was then purified by silica gel chromatography to give thecorresponding Weinreb amide.

Step 2: Grignard Addition to Weinreb Amide

The appropriate benzylmagnesium chloride (1.9 equiv) was added viasyringe to a solution of a Weinreb amide (1.0 equiv) in THF (0.5 M) at0° C. over 30 min. The reaction was stirred at 0° C. for 30 min and thenallowed to warm to room temperature over 1 h. The mixture was cooled to0° C. and quenched with 1.0 M aqueous HCl solution. The layers wereseparated, and the aqueous layer was extracted with ether. The combinedorganic layers was washed with water, washed with brine, dried overNa₂SO₄ (or MgSO₄), filtered, and concentrated to afford the crudeproduct. This crude product was then purified by silica gelchromatography to give the corresponding alkoxyaryl ketone.

General Procedure C Pd-Mediated Arylation of Ketones

A mixture of Pd₂ dba₃ (0.015 equiv), BINAP (0.035 equiv), and NaO^(t-)Bu(1.3 equiv) in a flask was placed under N₂ atmosphere by use of a vacuumand back-filling with N₂. THF (0.3 M) was added, followed by a solutionof the corresponding arylbromide (1.0 equiv) and 1.2 equivalents of a2-methoxyphenyl-ethanone (for example 1-(2,5-dimethoxyphenyl)ethanone)in THF (0.5 M). The resulting mixture was heated at 70° C. for 16 h.Water (100% v/v of THF) was added, and the mixture was extracted withether (3×). The combined organics were dried over anhydrous Na₂SO₄,filtered, and concentrated to give the crude product, which was purifiedby column chromatography on silica gel to give the correspondingalkoxyaryl ketone.

General Procedure D Step 1: Demethylation

Neat boron tribromide (3 equiv) was added dropwise to a solution ofalkoxyaryl ketone (1.0 equiv) in DCM (0.25M) at −78° C. The reactionmixture was allowed to warm to 0° C., stirred for 30 min, re-cooled to−78° C., and then carefully quenched with methanol (Note 1). The mixturewas allowed to warm to room temperature, washed with water, washed twicewith sat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄ (orMgSO₄), and concentrated to afford the crude product. This crude productwas then purified by silica gel chromatography to give the correspondingphenol.

Note 1:

In some instances, when the material crashes out of solution afterquenching with methanol, ethyl acetate is added to dissolve materialprior to work up.

Step 2: Protection of Phenol(s)

3,4-Dihydro-2H-pyran (5.0 equiv) was added to a mixture of dihydroxyarylketone (1 equiv) and pyridiniump-toluene sulfonate (0.20 equiv) in DCM(0.25M) at room temperature. The resulting mixture was stirred at thistemperature for 2-24 h. The mixture was washed with water, washed withsat'd aqueous NaHCO₃, dried over Na₂SO₄ (or MgSO₄), filtered, andconcentrated to afford the crude product. This crude product was thenpurified by silica gel chromatography to give the correspondingTHP-protected hydroxyarylketone.

Step 3: Cyclization to chromanone

A solution of protected hydroxyarylketone (1.0 equiv),4-iodoarylaldehyde (1.0 equiv), piperidine (0.35 equiv), and DBU (0.35equiv) in s-butanol (1.0 M) was heated at reflux. Using a Dean-Starktrap, half of the solvent was removed over 30-40 min, and the reactionwas kept at reflux without further concentration for an additional 4-8h. The reaction mixture was cooled to 90° C., i-propanol (0.7-1.0 foldof s-butanol v/v) was added, and the reaction was allowed to cool toroom temperature. Any large pieces of material were broken down with aspatula, and the suspension was stirred overnight (Note 1 & 2). Theprecipitate was collected by filtration to give the correspondingchromanone.

Note 1:

In some instances, the stirring time after cooling to room temperaturemay be longer (2-3 days).

Note 2:

In some instances, a work up procedure is used when no solidprecipitates out. The mixture is diluted with an organic solvent (DCM orEtOAc) and washed with water and washed with brine. The organic layerwas dried over Na₂SO₄ (or MgSO₄), filtered, and concentrated to affordthe crude product. This crude product was then purified by silica gelchromatography.

General Procedure E Step 1: Grignard Addition and Elimination

A solution of Grignard reagent (for example methyl magnesium chloride;3.75 equiv, 3M in THF) was added dropwise to a solution of chromanone (1equiv) in THF (0.25M) at 0° C. The reaction was stirred at 0° C. for15-30 min and allowed to warm to room temperature. After stirring for2-2.5 h, the solution was cooled to 0° C. and quenched with sat'daqueous ammonium chloride. The mixture was allowed to warm to roomtemperature, diluted with ethyl acetate and water, and the layers wereseparated. The organic layer was washed with water, dried over Na₂SO₄(or MgSO₄), filtered, and concentrated to yield the correspondingtertiary alcohol. This crude material was suspended in 80% aceticacid/H₂O (0.1 M) and heated at 90° C. for 3-5 days. The reaction mixturewas concentrated under reduced pressure and diluted with ethyl acetate(Note 1). The organic phase was washed with water, washed twice withsat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄ (or MgSO₄),filtered, and concentrated to afford the crude product. This crudeproduct was then purified by silica gel chromatography to give thecorresponding chromene.

Note 1:

In some instances, the reaction mixture was directly diluted with waterand extracted three times with ethyl acetate. The organic layers combineand washed twice with a water/brine mixture, washed twice with saturatedaqueous NaHCO₃, washed with brine, dried over Na₂SO₄, filtered, andconcentrated to afford the crude product. This crude product was thenpurified by silica gel chromatography to give the correspondingchromene.

Step 2: Protection of the Phenol(s)

3,4-Dihydro-2H-pyran (1.5-5 equiv) was added to a solution ofhydroxyaryl chromene (1.0 equiv) and pyridiniump-toluene sulfonate(0.20-0.25 equiv) in DCM (0.25 M) and stirred at room temperature for4-5 h. The mixture was washed with sat'd aqueous NaHCO₃, washed withwater, washed with brine, dried over Na₂SO₄ (or MgSO₄), filtered, andconcentrated to afford the crude product. This crude product was thenpurified by silica gel chromatography to give the correspondingTHP-protected chromene.

General Procedure F Ullmann Coupling

A mixture of THP-protected iodochromene (1.0 equiv), 1.5-2.0 equivalentsof the corresponding amino-alcohol side-chain (for example Intermediate7, 13 or 14), copper iodide (0.10 equiv), and potassium carbonate (2.0equiv) in butyronitrile (0.5 M) was degassed by bubbling nitrogenthrough the mixture for 15 min. The reaction mixture was heated at 125°C. for 1-5 days, allowed to cool to room temperature, and diluted withethyl acetate. The mixture was filtered through a pad of Celite andwashed with ethyl acetate. The organic phase was washed twice withwater, washed with brine, dried over Na₂SO₄ (or MgSO₄), filtered, andconcentrated to afford the crude product. This crude product was thenpurified by silica gel chromatography to give the corresponding Ullmanncoupled product.

Note:

In some cases: i) the reaction time varied depending on the aminoalcohol (overnight to 5 days; progress was monitored by LCMS), and ii)cesium carbonate was used instead of potassium carbonate.

General Procedure G Step 1: Ullmann Coupling

A mixture of THP-protected iodochromene (1.0 equiv), diol (4.0 equiv),copper iodide (0.10 equiv), 1,10-phenanthroline (0.20 equiv), andpotassium carbonate (2.0 equiv) in butyronitrile (0.5 M) was degassed.The reaction mixture was heated at 125° C. for 3 days, allowed to coolto room temperature, and diluted with ethyl acetate. The organic phasewas washed twice with water, washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the crude product. This crudeproduct was then purified by silica gel chromatography to give thecorresponding Ullmann product.

Step 2: Mesylation

Methanesulfonyl chloride (1.3 equiv) was added dropwise to a solution ofalcohol (1.0 equiv) and triethylamine (1.5 equiv) in DCM (0.1 M) at 0°C. The reaction mixture was stirred for 1 h at 0° C., then diluted withDCM, and quenched with 1N aqueous HCl. The layers were separated and theorganic layer was washed with water, washed with sat'd aqueous NaHCO₃,washed with brine, dried over Na₂SO₄, and concentrated to give thedesired mesylate.

Step 3: Alkylation

A suspension of mesylate (1.0 equiv), amine (2-3 equiv), and potassiumcarbonate (2.0 equiv) in acetonitrile (0.1 M) was heated at 80° C. for3-24 h. The reaction mixture was cooled to room temperature,concentrated under reduced pressure, and diluted with DCM (0.01M). Theresulting precipitate was filtered off and the filtrate was concentratedunder reduced pressure. This crude product was then purified by silicagel chromatography to give the corresponding alkylation product.

General Procedure H Cyanation of Aryl Halides and Removal of THPGroup(s)

A mixture of arylbromide (1.0 equiv), 1-butylimidazole (20.0 equiv),copper iodide (1.0 equiv), potassium ferrocyanide trihydrate (2.0equiv), and m-xylene (0.1 M) was degassed by 3 vacuum/nitrogen cycles.The reaction mixture was heated at 140° C. for 1-3 days. The mixture wasfiltered through a pad of Celite and washed with ethyl acetate. Thefiltrate was washed with water, washed with brine, dried over Na₂SO₄ (orMgSO₄), filtered, and concentrated under reduced pressure. The crudematerial was then purified by silica gel chromatography to give thecorresponding arylnitrile (Note 1). This purified material (1.0 equiv)was stirred in 80% acetic acid/H₂O (0.25 M) at room temperature for 3-24h. The solvent was removed under reduced pressure, and the residue waspurified by reverse-phase HPLC (Note 2). The purified fractions werepooled, concentrated under reduced pressure down to approximately thirdof volume, and extracted with ethyl acetate. The organic layer waswashed with sat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄(or MgSO₄), filtered, and concentrated under reduced pressure. Theresulting solid was dissolved in ethyl acetate (0.05 M) and treated withHCl (2N in diethyl ether, 2.0 equiv). The solvent was removed underreduced pressure to give the corresponding hydrochloride salt.

Note 1:

An alternative procedure may also be used: A mixture of arylbromide (orarylchloride) (1.0 equiv), zinc powder (0.72 equiv),[1,1′-binaphthalen]-2-yldi-tert-butylphosphine (0.30 equiv), zinccyanide (2.1 equiv), and dimethylacetamide (0.12-0.14 M) was degassed by3 vacuum/nitrogen cycles. Palladium trifluoroacetate (0.13 equiv) wasadded and degassed again with 3 additional vacuum/nitrogen cycles. Thereaction mixture was heated at 95° C. for 3.5-5 h, allowed to cool toroom temperature, and diluted with ethyl acetate. The organic phase waswashed twice with water, dried over Na₂SO₄ (or MgSO₄), filtered, andconcentrated to afford the crude product. This crude product was thenpurified by silica gel chromatography to give the correspondingarylnitrile.

Note 2:

For some compounds, after purification by reverse-phase HPLC, thefractions were concentrated down under reduced pressure to give thecorresponding trifluoroacetate salt without any further manipulation.

General Procedure I N-Alkylation

A mixture of amine (1.0 eq), alkyl iodide (1.5 eq) and sodiumbicarbonate (2.0 eq) in DMA was heated at 50° C. for 6 hrs, allowed tocool to RT and diluted with ethyl acetate. The organic extract waswashed with water, washed with brine, dried over Na₂SO₄ (or MgSO4),filtered, concentrated, and purified by silica gel chromatography togive the corresponding alkylation product.

Note 1:

In some instances, the reaction was heated at 80° C. to shorten thereaction time.

Note 2:

In some instances, additional alkyl iodide and sodium bicarbonate wereadded to drive the reaction to completion.

General Procedure J Removal of THP Protecting Group(s)

The THP protected chromene (1.0 equiv) was stirred in 80% aceticacid/H₂O (0.25 M) at room temperature for 3-24 h. The solvent wasremoved under reduced pressure, and the residue was purified byreverse-phase HPLC (Note 1 & 2). The purified fractions were pooled,concentrated under reduced pressure down to approximately third ofvolume, and extracted with ethyl acetate. The organic layer was washedwith sat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄ (orMgSO₄), filtered, and concentrated under reduced pressure. The resultingsolid was dissolved in ethyl acetate (0.05 M) and treated with HCl (2Nin diethyl ether, 2.0 equiv). The solvent was removed under reducedpressure to give the corresponding hydrochloride salt.

Note 1:

For some compounds, after purification by reverse-phase HPLC, thefractions were concentrated down under reduced pressure to give thecorresponding trifluoroacetate salt without any further manipulation.

Note 2:

For some instances, the residue was dissolved in ethyl acetate andwashed with sat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄(or MgSO₄), filtered, and concentrated under reduced pressure to givethe crude product. This crude product was purified by silica gelchromatography.

Example 12-(4-(2-(3-(Fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

A mixture of Intermediate 5 (0.11 g, 0.17 mmol), Intermediate 6 (0.32mg, 0.25 mmol), potassium carbonate (70 mg, 0.51 mmol) in acetonitrile(1.7 mL) was heated at 80° C. for 6 h, allowed to cool to roomtemperature, diluted with water (10 mL) and extracted with ethyl acetate(3×10 mL). The combined organic layers were washed with water, withbrine, dried over Na₂SO₄, and concentrated on a rotary evaporator toafford the crude3-(fluoromethyl)-1-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)azetidine.This crude material was stirred in 80% acetic acid/H₂O (5 mL) at roomtemperature for 3 h. The solvents were removed on a rotary evaporator,and the residue was dissolved in ethyl acetate. The organic layer waswashed with sat'd aqueous NaHCO₃, washed with brine, dried over Na₂SO₄,filtered, and concentrated under reduced pressure to give the crudeproduct. This crude material was then purified by reverse phase C18chromatography (30-40% acetonitrile/water/0.1% TFA). Fractions werepooled, concentrated and dissolved in ethyl acetate. The organic layerwas washed with sat'd aqueous NaHCO₃, washed with brine, dried overNa₂SO₄, filtered, and concentrated under reduced pressure to afford2-(4-(2-(3-(fluoromethyl)azetidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-olas pale yellow solid. ¹H NMR (DMSO-d₆): δ 9.40 (s, 1H), 8.94 (s, 1H),7.18 (d, 2H), 7.12 (t, 1H), 6.75 (d, 2H), 6.73 (m, 1H), 6.68-6.57 (m,2H), 6.60 (s, br, 1H), 6.47 (m, 2H), 5.82 (s, 1H), 4.53 (d, 1H), 4.41(d, 1H), 3.81 (t, 2H), 3.26 (dd, 2H), 2.94 (t, 2H), 2.76-2.64 (m, 1H),2.63 (t, 2H), 2.02 (s, 3H).; LCMS: 462 (M+H)⁺.

Example 22-(4-(2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

Step 1:(3R)-3-(Fluoromethyl)-1-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine

A mixture of Intermediate 3 (2.1 g, 3.35 mmol), Intermediate 13 (738 mg,5.02 mmol), copper iodide (127 mg, 0.67 mmol), and potassium carbonate(925 mg, 6.7 mmol) in butyronitrile (7 mL) was degassed three times andthen heated to 125° C. for 2 days. After cooling, ethyl acetate andwater were added and the two layers were separated. The organic layerwas washed with brine, dried over sodium sulfate, filtered and thesolvent removed. The residue was purified by flash chromatography onsilica gel (20 to 100% ethyl acetate/hexanes) to afford 1.87 g of(3R)-3-(fluoromethyl)-1-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidineas a yellow foam. LCMS: 644 (M+H)⁺.

Step 2:(R)-2-(4-(2-(3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

A mixture of(3R)-3-(fluoromethyl)-1-(2-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)ethyl)pyrrolidine(1.87 g, 2.9 mmol) in acetic acid (80% aq., 30 mL) was stirred at roomtemperature overnight. The acetic acid was removed and the residue waspartitioned between ethyl acetate and sat'd aqueous NaHCO₃. The organiclayer was washed with sat'd aqueous NaHCO₃, dried over sodium sulfate,filtered and the solvent removed. The residue was purified by flashchromatography on silica gel (0 to 5% methanol/dichloromethane) toafford 1.1 g of(R)-2-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-olas a pinkish foam. ¹H NMR (DMSO-d₆): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.18(d, 2H), 7.14 (t, 1H), 6.78 (d, 2H), 6.73 (s, 1H), 6.67-6.65 (m, 2H),6.65 (s, 1H), 6.49-6.45 (m, 2H), 5.83 (s, 1H), 4.35-4.30 (m, 1H),4.23-4.19 (m, 1H), 3.96 (t, 2H), 2.71 (t, 2H), 2.60 (t, 1H), 2.46-2.40(m, 3H), 2.36-2.31 (m, 1H), 2.02 (s, 3H), 1.83-1.76 (m, 1H), 1.39-1.30(m, 1H); LCMS: 476 (M+H)⁺.

Example 2a(R)-2-(4-(2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was the 1^(st) eluting diastereomer when Example 2was separated on a RegisCell (250×4.6 mm, 5 nm) column[hexanes/ethanol/diethylamine (75/25/0.1%)]. Diastereomericratio: >99:1. ¹H NMR (DMSO-d₆; HCl salt): δ 10.61 (br, 1H), 9.47 (s,1H), 8.98 (s, 1H), 7.23 (d, 2H), 7.12 (t, 1H), 6.86 (d, 2H), 6.74 (br,1H), 6.70-6.57 (m, 3H), 6.47-6.45 (m, 2H), 5.86 (s, 1H), 4.53-4.47 (m,1H), 4.46-4.36 (m, 1H), 4.25 (br, 2H), 3.73-3.49 (m, 3H), 3.34-3.22 (m,1H), 3.18-3.06 (m, 1H), 2.98-2.86 (m, 1H), 2.20-2.11 (m, 1H), 2.02 (s,3H), 1.87-1.75 (m, 1H), 1.67-1.55 (m, 1H). LCMS: 476.1 (M+H)⁺.

Example 2b(S)-2-(4-(2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was the 2^(nd) eluting diastereomer when Example 2was separated on a RegisCell (250×4.6 mm, 5 nm) column[hexanes/ethanol/diethylamine (75/25/0.1%)]. Diastereomericratio: >99:1. ¹H NMR (DMSO-d₆; HCl salt): δ 10.61 (br, 1H), 9.48 (s,1H), 8.98 (s, 1H), 7.24 (d, 2H), 7.12 (t, 1H), 6.86 (d, 2H), 6.75 (d,1H), 6.70-6.57 (m, 3H), 6.48-6.45 (m, 2H), 5.86 (s, 1H), 4.57-4.47 (m,1H), 4.45-4.35 (m, 1H), 4.30-4.22 (m, 2H), 3.75-3.50 (m, 3H), 3.33-3.21(m, 1H), 3.18-3.08 (m, 1H), 2.97-2.86 (m, 1H), 2.20-2.09 (m, 1H), 2.03(s, 3H), 1.86-1.74 (m, 1H), 1.66-1.58 (m, 1H). LCMS: 476.1 (M+H)⁺.

Example 32-(4-((S)-2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

Step 1:(3R)-3-(fluoromethyl)-1-(2S)-1-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)-phenoxy)propan-2-yl)pyrrolidine

A mixture of Intermediate 3 (1.0 g, 1.6 mmol), Intermediate 14 (388 mg,2.4 mmol), copper iodide (61 mg, 0.32 mmol), and potassium carbonate(443 g, 3.2 mmol) in butyronitrile (3.2 mL) was degassed three timeswith vacuum/nitrogen cycles. The reaction mixture was heated at 125° C.for 2 days, allowed to cool to room temperature, and diluted with ethylacetate. Insoluble material was filtered through Celite, and the Celitewas washed with ethyl acetate. The filtrate was washed twice with water,washed with brine, dried over Na₂SO₄, filtered, and concentrated underreduced pressure. The crude material was purified by silica gelchromatography (0-100% EtOAc/hexane) to give(3R)-3-(fluoromethyl)-1-((2S)-1-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)propan-2-yl)pyrrolidine(785 mg, 74%) as a beige foam. ¹H NMR (400 MHz, DMSO-d₆): δ 7.27-7.19(m, 3H), 6.99 (t, 1H), 6.93-6.88 (m, 3H), 6.81-6.76 (m, 3H), 6.59 (d,1H), 5.97 (d, 1H), 5.43-5.38 (dt, 1H), 5.34 (m, 1H), 4.32-4.30 (m, 1H),4.20-4.19 (m, 1H), 3.99-3.93 (m, 1H), 3.73-3.69 (m, 3H), 3.58-3.47 (m,2H), 2.69-2.60 (m, 2H), 2.59-2.52 (m, 2H), 2.45-2.30 (m, 2H), 2.06 (s,3H), 1.90-1.65 (m, 7H), 1.64-1.47 (m, 6H), 1.40-1.30 (m, 1H), 1.06 (d,3H); LCMS: 658.3 (M+H)⁺.

Step 2:2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

(3R)-3-(fluoromethyl)-1-((2S)-1-(4-(4-methyl-6-((tetrahydro-2H-pyran-2-yl)oxy)-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2H-chromen-2-yl)phenoxy)propan-2-yl)pyrrolidine(785 mg, 1.19 mmol) was stirred in 80% acetic acid/H₂O (6.0 mL) at roomtemperature for 2 days. The solvents were removed on a rotaryevaporator, and the residue was dissolved in ethyl acetate. The organiclayer was washed with sat'd aqueous NaHCO₃, washed with water, washedwith brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. This crude material was then purified by silica gelchromatography (0-4% MeOH/DCM) to afford2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol(410 mg, 70%) as pale pink solid. ¹H NMR (DMSO-d₆): δ 9.43 (s, 1H), 8.94(s, 1H), 7.18 (d, 2H), 7.12 (t, 1H), 6.79 (d, 2H), 6.73 (m, 1H), 6.68(dt, 1H), 6.65 (m, 1H), 6.61 (m, 1H), 6.49-6.45 (m, 2H), 5.83 (s, 1H),4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H), 3.99-3.93 (m, 1H), 3.74-3.70 (m,1H), 2.69-2.60 (m, 2H), 2.58-2.52 (m, 2H), 2.45-2.32 (m, 2H), 2.02 (s,3H), 1.82-1.75 (m, 1H), 1.36-1.30 (m, 1H), 1.07 (d, 3H); LCMS: 490.2(M+H)⁺.

Example 3a(R)-2-(4-((S)-2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was the 1^(st) eluting diastereomer when Example 3was separated on a RegisCell (250×4.6 mm, 5 μm) column[hexanes/ethanol/diethylamine (75/25/0.1%)]. Diastereomericratio: >99:1. ¹H NMR (DMSO-d₆; salt): δ 10.60 (br, 1H), 9.47 (s, 1H),8.98 (s, 1H), 7.24 (d, 2H), 7.12 (t, 1H), 6.87 (d, 2H), 6.74 (d, 1H),6.70-6.60 (m, 3H), 6.48-6.45 (m, 2H), 5.86 (s, 1H), 4.56-4.47 (m, 1H),4.47-4.36 (m, 1H), 4.20-4.15 (m, 2H), 3.74-3.66 (m, 1H), 3.62-3.49 (m,2H), 3.28-3.12 (m, 1H), 3.03-2.90 (m, 1H), 2.15-2.07 (m, 1H), 2.03 (s,3H), 1.84-1.73 (m, 1H), 1.66-1.55 (m, 1H), 1.35 (d, 3H); LCMS: 490.1(M+H)⁺.

Example 3b(S)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was the 2^(nd) eluting diastereomer when Example 3was separated on a RegisCell (250×4.6 mm, 5 μm) column[hexanes/ethanol/diethylamine (75/25/0.1%)]. Diastereomericratio: >99:1. ¹H NMR (DMSO-d₆, HCl salt): δ 10.65-10.60 (br, 1H), 9.47(s, 1H), 8.98 (s, 1H), 7.24 (d, 2H), 7.12 (t, 1H), 6.87 (d, 2H), 6.74(d, 1H), 6.70-6.63 (m, 3H), 6.48-6.45 (m, 2H), 5.86 (s, 1H), 4.56-4.47(m, 1H), 4.45-4.35 (m, 1H), 4.22-4.11 (m, 2H), 3.74-3.64 (m, 1H),3.62-3.49 (m, 2H), 3.28-3.12 (m, 1H), 3.03-2.90 (m, 1H), 2.15-2.07 (m,1H), 2.03 (s, 3H), 1.84-1.73 (m, 1H), 1.66-1.55 (m, 1H), 1.35 (d, 3H);LCMS: 490.1 (M+H)⁺.

Example 43-(4-Chlorophenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, G and J (z=0) using 1,4-dimethoxybenzene and2-(4-chlorophenyl)acetic acid in general procedure A, and Intermediate 8in general procedure G. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 7.40(m, 2H), 7.31 (m, 2H), 7.19 (d, 2H), 6.78 (m, 2H), 6.75 (m, 1H),6.52-6.47 (m, 2H), 5.91 (s, 1H), 4.33-4.30 (m, 1H), 4.21-4.18 (m, 1H),3.95 (t, 2H), 2.70 (t, 2H), 2.59 (t, 1H), 2.55-2.47 (m, 1H), 2.50-2.40(m, 2H), 2.35-2.31 (m, 1H), 1.98 (s, 3H), 1.83-1.77 (m, 1H), 1.37-1.32(m, 1H); LCMS: 494.1 (M+H)⁺.

Example 53-(3-Fluoro-4-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, F and J (z=1) using 1,4-dimethoxybenzene and2-(3-fluoro-4-methoxyphenyl)acetic acid in general procedure A andIntermediate 13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95(s, 1H), 8.93 (s, 1H), 7.17 (d, 2H), 7.09 (m, 1H), 6.93-6.86 (m, 2H),6.77 (m, 2H), 6.71 (m, 1H), 6.46 (m, 2H), 5.89 (s, 1H), 4.32-4.30 (m,1H), 4.20-4.18 (m, 1H), 3.95 (t, 2H), 2.69 (t, 2H), 2.59 (t, 1H),2.55-2.47 (m, 1H), 2.48-2.42 (m, 2H), 2.35-2.31 (m, 1H), 2.03 (s, 3H),1.83-1.78 (m, 1H), 1.37-1.34 (m, 1H); LCMS: 494.1 (M+H)⁺.

Example 63-(3,4-Difluoro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and5-bromo-1,2-difluoro-3-methoxybenzene in general procedure C andIntermediate 13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ10.45 (br s, 1H), 8.97 (s, 1H), 7.17 (d, 2H), 6.81-6.74 (m, 4H), 6.61(m, 1H), 6.51-6.46 (m, 2H), 5.83 (s, 1H), 4.33-4.28 (m, 1H), 4.23-4.16(m, 1H), 3.96 (t, 2H), 2.70 (t, 2H), 2.61 (t, 1H), 2.55-2.47 (m, 2H),2.48-2.42 (m, 1H), 2.36-2.32 (m, 1H), 2.02 (s, 3H), 1.85-1.76 (m, 1H),1.39-1.31 (m, 1H); LCMS: 512.1 (M+H)⁺.

Example 73-(2-Fluoro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and2-bromo-1-fluoro-4-methoxybenzene in general procedure C andIntermediate 13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41(s, 1H), 8.98 (s, 1H), 7.19 (d, 2H), 6.99 (t, 1H), 6.79 (d, 2H), 6.74(d, 1H), 6.68-6.64 (m, 1H), 6.54-6.47 (m, 3H), 5.77 (s, 1H), 4.33-4.30(m, 1H), 4.21-4.18 (m, 1H), 3.96 (t, 2H), 2.70 (t, 2H), 2.60 (t, 1H),2.55-2.47 (m, 1H), 2.48-2.42 (m, 2H), 2.34-2.32 (m, 1H), 1.92 (s, 3H),1.83-1.78 (m, 1H), 1.38-1.33 (m, 1H); LCMS: 494.1 (M+H)⁺

Example 83-(4-Fluoro-3-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and4-bromo-1-fluoro-2-methoxybenzene in general procedure C andIntermediate 13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.87(s, 1H), 8.94 (s, 1H), 7.17 (d, 2H), 7.11-7.06 (m, 1H), 6.79 (m, 3H),6.73 (m, 1H), 6.68-6.65 (m, 1H), 6.48-6.45 (m, 2H), 5.81 (s, 1H),4.31-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.96 (t, 2H), 2.70 (t, 2H), 2.62(t, 1H), 2.55-2.47 (m, 1H), 2.48-2.42 (m, 2H), 2.35-2.32 (m, 1H), 2.01(s, 3H), 1.83-1.79 (m, 1H), 1.37-1.33 (m, 1H); LCMS: 494.1 (M+H)⁺

Example 93-(3,4-Difluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and5-bromo-1,2-difluoro-3-methoxybenzene in general procedure C andIntermediate 14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ10.45 (br s, 1H), 8.97 (s, 1H), 7.17 (d, 2H), 6.81-6.74 (m, 4H), 6.61(m, 1H), 6.51-6.46 (m, 2H), 5.83 (s, 1H), 4.33-4.30 (m, 1H), 4.21-4.19(m, 1H), 3.99-3.94 (m, 1H), 3.73 (m, 1H), 2.69-2.53 (m, 4H), 2.41-2.32(m, 2H), 2.02 (s, 3H), 1.82-1.77 (m, 1H), 1.36-1.32 (m, 1H), 1.07 (d,3H); LCMS: 526.1 (M+H)⁺.

Example 103-(3-Fluoro-5-hydroxyphenyl)-2-(4-(2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and1-bromo-3-fluoro-5-methoxybenzene in general procedure C andIntermediate 13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95(s, 1H), 8.96 (s, 1H), 7.18 (d, 2H), 6.81 (d, 2H), 6.74 (d, 1H),6.55-6.52 (dt, 1H), 6.51-6.43 (m, 4H), 5.84 (s, 1H), 4.33-4.30 (m, 1H),4.21-4.18 (m, 1H), 3.96 (t, 2H), 2.70 (t, 2H), 2.62 (t, 1H), 2.55-2.47(m, 1H), 2.48-2.42 (m, 2H), 2.35-2.32 (m, 1H), 2.03 (s, 3H), 1.83-1.78(m, 1H), 1.39-1.33 (m, 1H); LCMS: 494.1 (M+H)⁺

Example 113-(4-Fluoro-3-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and4-bromo-1-fluoro-2-methoxybenzene in general procedure C andIntermediate 14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.87(s, 1H), 8.95 (s, 1H), 7.17 (d, 2H), 7.11-7.06 (m, 1H), 6.79 (m, 3H),6.73 (m, 1H), 6.69-6.65 (m, 1H), 6.50-6.45 (m, 2H), 5.81 (s, 1H),4.33-4.30 (m, 1H), 4.21-4.18 (m, 1H), 3.97-3.93 (m, 1H), 3.73-3.71 (m,1H), 2.69-2.60 (m, 2H), 2.58-2.54 (m, 2H), 2.41-2.35 (m, 2H), 2.01 (s,3H), 1.80-1.78 (m, 1H), 1.40-1.33 (m, 1H), 1.07 (d, 3H); LCMS: 508.1(M+H)⁺

Example 123-(3-Fluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and1-bromo-3-fluoro-5-methoxybenzene in general procedure C andIntermediate 14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95(s, 1H), 8.96 (s, 1H), 7.18 (d, 2H), 6.80 (d, 2H), 6.74 (d, 1H),6.55-6.52 (dt, 1H), 6.51-6.43 (m, 4H), 5.84 (s, 1H), 4.33-4.30 (m, 1H),4.21-4.19 (m, 1H), 3.98-3.94 (m, 1H), 3.73-3.71 (m, 1H), 2.67-2.60 (m,2H), 2.58-2.54 (m, 2H), 2.38-2.35 (m, 2H), 2.03 (s, 3H), 1.85-1.74 (m,1H), 1.40-1.33 (m, 1H), 1.07 (d, 3H); LCMS: 508.1 (M+H)⁺

Example 133-(3-Fluoro-4-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, F and J (z=1) using 1,4-dimethoxybenzene and2-(3-fluoro-4-methoxyphenyl)acetic acid in general procedure A andIntermediate 14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.95(s, 1H), 8.93 (s, 1H), 7.17 (d, 2H), 7.10-7.07 (m, 1H), 6.93-6.86 (m,2H), 6.78 (d, 2H), 6.71 (t, 1H), 6.46 (m, 2H), 5.89 (s, 1H), 4.32-4.30(m, 1H), 4.20-4.18 (m, 1H), 3.96-3.92 (m, 1H), 3.74-3.70 (m, 1H),2.66-2.60 (m, 2H), 2.58-2.52 (m, 2H), 2.38-2.35 (m, 2H), 2.03 (s, 3H),1.80-1.78 (m, 1H), 1.35-1.33 (m, 1H), 1.06 (d, 3H); LCMS: 508.1 (M+H)⁺.

Example 143-(2-Fluoro-5-hydroxyphenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures C,D, E, F and J (z=1) using 1-(2,5-dimethoxyphenyl)ethanone and2-bromo-1-fluoro-4-methoxybenzene in general procedure C andIntermediate 14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41(s, 1H), 8.98 (s, 1H), 7.19 (d, 2H), 6.99 (t, 1H), 6.79 (d, 2H), 6.74(d, 1H), 6.68-6.64 (m, 1H), 6.52-6.46 (m, 3H), 5.76 (s, 1H), 4.32-4.30(m, 1H), 4.20-4.19 (m, 1H), 3.96-3.93 (m, 1H), 3.93-3.71 (m, 1H),2.67-2.60 (m, 2H), 2.58-2.52 (m, 2H), 2.48-2.35 (m, 2H), 1.91 (s, 3H),1.87-1.73 (m, 1H), 1.38-1.33 (m, 1H), 1.07 (d, 3H); LCMS: 508.1 (M+H)⁺

Example 153-(4-Chlorophenyl)-2-(4-((S)-2-((R)-3-(fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, F and J (z=0) using 1,4-dimethoxybenzene and2-(4-chlorophenyl)acetic acid in general procedure A and Intermediate 14in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 7.40(m, 2H), 7.31 (m, 2H), 7.18 (d, 2H), 6.78 (m, 2H), 6.75 (m, 1H),6.51-6.47 (m, 2H), 5.92 (s, 1H), 4.32-4.30 (m, 1H), 4.21-4.18 (m, 1H),3.96-3.92 (m, 1H), 3.74-3.69 (m, 1H), 2.68-2.60 (m, 2H), 2.59-2.52 (m,2H), 2.48-2.35 (m, 2H), 2.02 (s, 3H), 1.81-1.76 (m, 1H), 1.36-1.31 (m,1H), 1.06 (d, 3H); LCMS: 508.1 (M+H)⁺.

Example 164-(2-(4-((S)-2-(R)-3-(Fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-6-hydroxy-4-methyl-2H-chromen-3-yl)benzonitrile

The title compound was synthesized as described in general procedures A,D, E, F and H (z=0) using 1,4-dimethoxybenzene and2-(4-chlorophenyl)acetic acid in general procedure A and Intermediate 14in general procedure F. ¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 7.81(d, 2H), 7.50 (d, 2H), 7.19 (d, 2H), 6.79 (d, 3H), 6.52-6.49 (m, 2H),5.98 (s, 1H), 4.31-4.30 (m, 1H), 4.20-4.18 (m, 1H), 3.96-3.93 (m, 1H),3.73-3.72 (m, 1H), 2.66-2.60 (m, 2H), 2.57-2.52 (m, 2H), 2.41-2.35 (m,2H), 2.03 (s, 3H), 1.85-1.75 (m, 1H), 1.34-1.33 (m, 1H), 1.06 (d, 3H);LCMS: 499.1 (M+H)⁺.

Example 172-(4-(2-(4-Fluoropiperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures Gand J (z=1) using 4-fluoropiperidine hydrochloride and Intermediate 3.¹H NMR (DMSO-d₆): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.18 (d, 2H), 7.13 (t,1H), 6.79 (d, 2H), 6.73 (m, 1H), 6.78 (d, 1H), 6.65 (dd, 1H), 6.62 (m,1H), 6.47 (m, 2H), 5.83 (s, 1H), 4.72-4.53 (m, 1H), 3.97 (t, 2H), 2.63(t, 2H), 2.60-2.53 (m, 2H), 2.38-2.28 (m, 2H), 2.03 (s, 3H), 1.88-1.73(m, 2H), 1.71-1.58 (m, 2H); LCMS: 476.2 (M+H)⁺.

Example 182-(4-(2-((S)-2-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures Gand J (z=1) using Intermediate 3 and Intermediate 9. ¹H NMR (DMSO-d₆;TFA salt): δ 9.88 (s, 1H), 9.43 (br, 1H), 9.00 (br, 1H), 7.24 (d, 2H),7.13 (t, 1H), 6.86 (d, 2H), 6.74 (m, 1H), 6.69 (d, 1H), 6.65 (dd, 1H),6.62 (m, 1H), 6.46 (m, 2H), 5.88 (s, 1H), 4.88-4.59 (m, 2H), 4.24 (m,2H), 4.00-3.84 (m, 1H), 3.73-3.44 (m, 3H), 3.26 (m, 1H), 2.20-2.08 (m,1H), 2.03 (s, 3H), 2.05-1.95 (m, 1H), 1.90-1.79 (m, 1H), 1.78-1.67 (m,1H); LCMS: 476.1 (M+H)⁺.

Example 192-(4-(2-(4-(Fluoromethyl)piperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures Gand J (z=1) using Intermediate 3 and Intermediate 10. ¹H NMR (DMSO-d₆):δ 9.44 (s, 1H), 8.94 (s, 1H), 7.18 (d, 2H), 7.13 (t, 1H), 6.78 (d, 2H),6.74 (m, 1H), 6.69 (m, 1H), 6.65 (m, 1H), 6.62 (m, 1H), 6.48 (m, 2H),5.83 (s, 1H), 4.26 (dd, 2H), 3.95 (t, 2H), 2.93-2.87 (m, 1H), 2.61 (t,2H), 2.03 (s, 3H), 2.00-1.92 (m, 2H), 1.62-1.53 (m, 3H), 1.22-1.13 (m,3H); LCMS: 490.1 (M+H)⁺.

Example 202-(4-(2-((R)-3-(Fluoromethyl)piperidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures Gand J (z=1) using Intermediate 3 and Intermediate 11. ¹H NMR (DMSO-d₆):δ 9.43 (s, 1H), 8.94 (s, 1H), 7.21 (d, 2H), 7.13 (t, 1H), 6.79 (d, 2H),6.73 (m, 1H), 6.68 (m, 1H), 6.65 (m, 1H), 6.61 (m, 1H), 6.47 (m, 2H),5.83 (s, 1H), 4.38-4.17 (m, 2H), 3.97 (t, 2H), 2.87-2.82 (m, 1H),2.78-2.72 (m, 1H), 2.62 (t, 2H), 2.03 (s, 3H), 2.02-1.93 (m, 1H),1.90-1.80 (m, 2H), 1.64-1.54 (m, 2H), 1.48-1.37 (m, 1H), 1.02-0.92 (m,1H); LCMS: 490.2 (M+H)⁺.

Example 21(R)-2-(4-(2-(3-(Difluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures Gand J (z=1) using Intermediate 3 and Intermediate 12. ¹H NMR (400 MHz,DMSO-d₆) δ 9.43 (s, 1H), 8.94 (s, 1H), 7.19 (d, 2H), 7.12 (t, 1H), 6.78(d, 2H), 6.73 (s, 1H), 6.69-6.60 (m, 3H), 6.47 (m, 2H), 5.92 (td, 1H),5.83 (s, 1H), 3.96 (t, 2H), 2.73-2.64 (m, 3H), 2.54-2.44 (m, 4H), 2.02(s, 3H), 1.83 (m, 1H), 1.61 (m, 1H); LCMS: 494 (M+H)⁺.

Example 222-(4-(2-((3-Fluoropropyl)(methyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures F,I and J (z=1) using Intermediate 3 and 2-(methylamino)ethanol in generalprocedure F, and 1-fluoro-3-iodopropane in general procedure I. ¹H NMR(400 MHz, DMSO-d₆): δ 9.44 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t,1H), 6.79 (d, 2H), 6.75-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H),6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.38 (t,1H), 3.95 (t, 2H), 2.65 (t, 2H), 2.44 (t, 2H), 2.19 (s, 3H), 2.03 (s,3H), 1.81-1.72 (m, 1H), 1.72-1.69 (m, 1H). LCMS: 464.2 (M+H)⁺.

Example 232-(4-(2-(Ethyl(2-fluoroethyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures F,I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in generalprocedure F, and 1-fluoro-2-iodoethane in general procedure I. ¹H NMR(400 MHz, DMSO-d₆): δ 9.46 (s, 1H), 8.95 (s, 1H), 7.19 (d, 2H), 7.13 (t,1H), 6.78 (d, 2H), 6.76-6.71 (m, 1H), 6.78 (d, 1H), 6.78-6.62 (m, 1H),6.62-6.60 (m, 1H), 6.58 (s, 2H), 5.83 (s, 1H), 4.50 (t, 1H), 4.38 (t,1H), 3.92 (t, 2H), 2.83-2.77 (m, 3H), 2.74 (t, 1H), 2.58 (q, 2H), 2.03(s, 3H), 0.94 (t, 3H). LCMS: 464.1 (M+H)⁺.

Example 242-(4-(2-(Ethyl(3-fluoropropyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures F,I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in generalprocedure F, and 1-fluoro-3-iodopropane in general procedure I. ¹H NMR(400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.19 (d, 2H), 7.13 (t,1H), 6.78 (d, 2H), 6.76-6.72 (m, 1H), 6.68 (d, 1H), 6.67-6.62 (m, 1H),6.62-6.60 (m, 1H), 6.48 (s, 2H), 5.84 (s, 1H), 4.50 (t, 1H), 4.39 (t,1H), 3.91 (t, 2H), 2.72 (t, 2H), 2.58-2.45 (m, 4H), 2.03 (s, 3H),1.80-1.71 (m, 1H), 1.71-1.65 (m, 1H), 0.93 (t, 3H). LCMS: 478.1 (M+H)⁺.

Example 252-(4-(2-(Ethyl(3,3,3-trifluoropropyl)amino)ethoxy)phenyl)-3-(3-hydroxyphenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures F,I and J (z=1) using Intermediate 3 and 2-(ethylamino)ethanol in generalprocedure F, and 1,1,1-trifluoro-3-iodopropane in general procedure I.¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H), 8.94 (s, 1H), 7.20 (d, 2H),7.13 (t, 1H), 6.78 (d, 2H), 6.75-6.71 (m, 1H), 6.68 (d, 1H), 6.66-6.62(m, 1H), 6.62-6.60 (m, 1H), 6.46 (s, 2H), 5.84 (s, 1H), 3.93 (t, 2H),2.76 (t, 2H), 2.70 (t, 2H), 2.57-2.49 (m, 2H), 2.45-2.31 (m, 2H), 2.03(s, 3H), 0.94 (t, 3H). LCMS: 514.1 (M+H)⁺.

Example 262-(4-(2-((R)-3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)phenyl)-3-(4-fluorophenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, F and J (z=0) using 1,4-dimethoxybenzene and2-(4-fluorophenyl)acetic acid in general procedure A, and Intermediate13 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H),7.35-7.29 (m, 2H), 7.22-7.13 (m, 4H), 6.78 (d, 2H), 6.75 (s, 1H), 6.49(s, 2H), 5.91 (s, 1H), 4.35-4.28 (m, 1H), 4.25-4.16 (m, 1H), 3.96 (t,2H), 2.70 (t, 2H), 2.60 (t, 1H), 2.57-2.38 (m, 3H), 2.37-2.30 (m, 1H),2.01 (s, 3H), 1.87-1.76 (m, 1H), 1.41-1.30 (m, 1H). LCMS: 478.1 (M+H)⁺.

Example 272-(4-((S)-2-(R)-3-(Fluoromethyl)pyrrolidin-1-yl)propoxy)phenyl)-3-(4-fluorophenyl)-4-methyl-2H-chromen-6-ol

The title compound was synthesized as described in general procedures A,D, E, F, and J (z=0) using 1,4-dimethoxybenzene and2-(4-fluorophenyl)acetic acid in general procedure A, and Intermediate14 in general procedure F. ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H),7.35-7.29 (m, 2H), 7.22-7.14 (m, 4H), 6.79 (d, 2H), 6.76-6.73 (m, 1H),6.52-6.46 (m, 2H), 5.91 (s, 1H), 4.36-4.28 (m, 1H), 4.24 (m, 1H), 3.99(m, 1H), 3.76-3.69 (m, 1H), 2.70-2.51 (m, 4H), 2.43-2.31 (m, 2H), 2.02(s, 3H), 1.88-1.75 (m, 1H), 1.40-1.30 (m, 1H), 1.07 (d, 3H). LCMS: 492.2(M+H)⁺.

Example 28(R)-1-(4-(2-(3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol

Step 1:5-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-iodobenzyl)-3-methyl-1H-indole

A solution of 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole(4.2 g, 10 mmol; see PCT/US98/21609 for synthesis) in DMF (40 mL) wascooled to 0° C. under nitrogen atmosphere. Sodium hydride (60%dispersion in mineral oil; 420 mg, 10.5 mmol) was added in one portion.The reaction mixture was stirred at 0° C. for 5 min, and then ice bathwas removed and allowed to warm to room temperature. After 1 h, thereaction was cooled back to 0° C. and 4-iodobenzyl bromide (3.7 g, 12.5mmol) was added slowly. After 5 minutes, the ice bath was removed andthe reaction mixture was stirred at room temperature for 6 h. Thereaction was diluted with water (200 mL), and ethyl acetate. Theprecipitate was sonicated, filtered off and dried to give 1.99 g of thedesired product. The filtrate was extracted with ethyl acetate (50 mL),the organic layer was washed with water, washed with brine and dried(MgSO₄), filtered, concentrated and purified by silica gelchromatography (20%-70% DCM in hexanes) to afford 2.62 g. The reactionresulted in total 4.6 g of5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-iodobenzyl)-3-methyl-1H-indoleas a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.56 (d, 2H), 7.51-7.46(m, 4H), 7.44-7.38 (m, 4H), 7.38-7.32 (m, 2H), 7.29 (d, 2H), 7.16 (d,1H), 7.16-7.10 (m, 3H), 6.82 (dd, 1H), 6.62 (d, 2H), 5.20 (s, 2H), 5.14(d, 4H), 2.17 (s, 3H).

Step 2:2-(4-((5-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol

A mixture of5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-iodobenzyl)-3-methyl-1H-indole(1.01 g, 1.58 mmol), ethylene glycol (0.44 mL, 7.89 mmol), copper iodide(32 mg, 0.17 mmol), 1,10-phenanthroline (60 mg, 0.33 mmol), andpotassium carbonate (436 mg, 3.15 mmol) in butyronitrile (3 mL) wasdegassed with three vacuum/N₂ cycles. The reaction was heated at 125° C.for 26 hrs and upon completion, allowed to cool to room temperature. Itwas then diluted with water. The aqueous layer was extracted three timeswith ethyl acetate. The combined ethyl acetate extracts were washed withwater (40 mL) and brine (40 mL), dried (MgSO₄), filtered, concentratedand purified by silica gel chromatography (0%-40% ethyl acetate inhexanes) to give 554 mg of2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanolas a pale yellow foam. ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (d, 4H),7.45-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H),7.15-7.10 (m, 3H), 6.81 (dd, 1H), 6.74 (s, 4H), 5.20-5.10 (m, 6H), 4.81(t, 1H), 3.87 (t, 2H), 3.64 (q, 2H), 2.16 (s, 3H). LCMS: 570.0 (M+H)⁺.

Step 3:2-(4-(5-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethylmethanesulfonate

A solution of2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol(546 mg, 0.96 mmol) in DCM (10 mL) was cooled to 0° C. Triethylamine(0.2 mL, 1.43 mmol) and methanesulfonyl chloride (0.1 mL, 1.29 mmol)were added and the reaction was stirred at 0° C. for 1 h. The reactionwas diluted with DCM (30 mL) and then washed with 1M HCl (20 mL), washedwith water (20 mL), dried (MgSO₄), filtered and concentrated undervacuum to give 597 mg of2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethylmethanesulfonate as a yellow foam. ¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (d,4H), 7.44-7.37 (m, 4H), 7.37-7.32 (m, 2H), 7.30 (d, 2H), 7.21 (d, 1H),7.15-7.10 (m, 3H), 6.83-6.74 (m, 5H), 5.20-5.10 (m, 6H), 4.50-4.45 (m,2H), 4.17-4.11 (m, 2H), 2.16 (s, 3H). LCMS: 648.1 (M+H)⁺.

Step 4:(R)-5-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole

A mixture of2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethylmethanesulfonate, (R)-3-(fluoromethyl)pyrrolidine (Intermediate 8) andpotassium carbonate in acetonitrile was degassed with three vacuum/N₂cycles. The reaction was heated at 80° C. for 10 hrs, allowed to cool toroom temperature and then diluted with water (40 mL). The aqueous layerwas extracted with ethyl acetate (2×40 mL) and the combined ethylacetate extracts were then washed with water (40 mL), washed with brine(40 mL), dried (MgSO₄), filtered, concentrated and purified by silicagel chromatography (0%-5% MeOH in DCM) to give 274 mg of(R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole.¹H NMR (400 MHz, DMSO-d₆): δ 7.48 (d, 4H), 7.44-7.37 (m, 4H), 7.37-7.32(m, 2H), 7.30 (d, 2H), 7.21 (d, 1H), 7.15-7.10 (m, 3H), 6.81 (dd, 1H),6.74 (s, 4H), 5.17-5.10 (m, 6H), 4.33-4.30 (m, 1H), 4.22-4.18 (m, 1H),3.94 (t, 2H), 2.70 (t, 2H), 2.56-2.40 (m, 3H), 2.60 (t, 1H), 2.36-2.31(m, 1H), 2.16 (s, 3H), 1.86-1.76 (m, 1H), 1.40-1.30 (m, 1H). LCMS: 655.3(M+H)⁺.

Step 5:(R)-1-(4-(2-(3-(Fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol

A solution of(R)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-3-methyl-1H-indole(263 mg, 0.40 mmol) in ethyl acetate/ethanol (4:1, 6 mL) was degassedwith three vacuum/N₂ cycles. To this solution was added 10% Pd on carbon(120 mg, 0.11 mmol) and then the needle of a H₂ balloon was placed intothe reaction flask. The mixture was stirred at room temperature for 15hrs then diluted with ethyl acetate, filtered through Celite andconcentrated. The residue was dried further on high vacuum to give 171mg of(R)-1-(4-(2-(3-(fluoromethyl)pyrrolidin-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-olas a beige solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.67 (s, 1H), 8.69 (s,1H), 7.16 (d, 2H), 7.06 (d, 1H), 6.85 (d, 2H), 6.80 (d, 1H), 6.75 (s,4H), 6.57 (dd, 1H), 5.10 (s, 2H), 4.35-4.30 (m, 1H), 4.23-4.18 (m, 1H),3.94 (t, 2H), 2.70 (t, 2H), 2.62 (t, 1H), 2.56-2.40 (m, 3H), 2.38-2.31(m, 1H), 2.10 (s, 3H), 1.87-1.76 (m, 1H), 1.40-1.31 (m, 1H). LCMS: 475.2(M+H)⁺.

Example 29 3×ERE MCF-7 Reporter Assay

MCF7 cells were maintained in RPMI 1640 supplemented with 10% FCS.Transcriptional assays were performed by seeding 100 μL of cells at adensity of 250,000 cells/mL into 96-well cell culture plates in RPMI1640 supplemented with 10% charcoal stripped serum and allowed to attachovernight. Cells were transiently transfected using Lipofectin (LifeTechnologies) according to the manufacturer's protocol. Triplicatetransfections were performed using 300 ng 3×ERE-TK-Luc (reportervector), 50 ng CMVpRL (normalization vector), and 130 ng pCMX (fillerDNA). Transfected cells were incubated overnight then treated withligand. For ER agonist assays, the compounds were serially diluted and50 μL of compound plus RPMI 1640 supplemented with charcoal strippedserum was added to the cells. For ER antagonist assays, the compoundswere serially diluted and 50 μL of compound with RPMI plus 17β-estradiolsupplemented with charcoal stripped serum were added to the cells. Thefinal 17β-estradiol concentration used in the antagonist assays was 0.1nM. Following 24 hour incubation the medium was removed and the cellswere lysed in 40 μL of lysis buffer (25 mM Tris Phosphate, 2 mM CDTA,10% Glycerol, 0.5% Triton X-100, 2 mM DTT). Firefly luciferase activitywas measured immediately following the addition of 40 μL luciferasebuffer (20 mM tricine, 0.1 mM EDTA, 1.07 mM (MgCO₃)₄Mg(OH)₂.5H₂O, 2.67mM MgSO₄, 33.3 mM DTT, 270 μM Coenzyme A, 470 μM luciferin, 530 μM ATP).Renilla luciferase was measured following the addition of 40 μLcolelenterazine buffer (1.1 M NaCl, 2.2 mM Na₂EDTA, 0.22 M KxPO₄ (pH5.1), 0.44 mg/mL BSA, 1.3 mM NaN₃, 1.43 μM coelenterazine, final pHadjusted to 5.0).

Example 30 Breast Cancer Cell Viability Assays

MCF-7 cells were adjusted to a concentration of 20,000 cells per mL inRPMI containing 10% FBS and 20 mM HEPES. 16 microliters of the cellsuspension (320 cells) was added to each well of a 384 well plate, andthe cells were incubated overnight to allow the cells to adhere. Thefollowing day an eleven point, serial semilog dilution of each compoundwas added to the cells in 16 μL at a final concentration ranging from0.3-0.000003 μM. After 5 days' compound exposure, 16 μL of CellTiter-GLo(Promega, Madison Wis.) was added to the cells the relative luminescenceunits (RLUs) of each well was determined. CellTiter-Glo added to 32 μLof medium without cells was used to obtain a background value. ThePercent viability of each sample was determined as follows: (RLUsample-RLU background/RLU untreated cells-RLU background)×100=%viability.

Viability effects in additional ER+ breast cancer cell lines, includingBT474, CAMA1, MDA-MB-361, ZR-75-1, T47D, can be profiled in assayssimilar to Example 30.

Illustrative biological data for representative compounds disclosedherein is presented in the following table:

TABLE 3 MCF7 Viability Assay MCF7 Viability Assay Example IC₅₀ MaxResponse  1 A ++  2 A ++  2a B ++  2b A ++  3 A ++  3a B ++  3b A ++  4B ++  5 A ++  6 A ++  7 A ++  8 B ++  9 A ++ 10 A ++ 11 A ++ 12 A ++ 13A ++ 14 A ++ 15 B ++ 16 B ++ 17 A ++ 18 B ++ 19 A ++ 20 A + 21 A ++ 22A + 23 B ++ 24 A ++ 25 B + 26 B ++ 27 B ++ 28 A ++ A = single IC₅₀ ≦ 1nM; B = single IC₅₀ > 1 nM; + = a single % value < 50%; ++ = a single %value ≧ 50%

Example 31 Breast Cancer Cell ER-α in Cell Western Assay (SP1)

MCF-7 cells were adjusted to a concentration of 200,000 cells per mL inRPMI containing 10% charcoal-stripped FBS and 20 mM HEPES. 16microliters of the cell suspension (3200 cells) was added to each wellof a poly-D-lysine 384 well plate, and the cells were incubatedovernight to allow the cells to adhere. The following day an elevenpoint, serial semilog dilution of each compound was added to the cellsin 16 μL at a final concentration ranging from 0.3-0.000003 μM. At 4 or24 hr post compound addition, the cells were fixed (10% formalin in PBS)for 20 minutes. Cells were permeablized in PBS 0.1% Triton and blockedwith LICOR blocking buffer (50 μl/well, 90′). The wells were thenincubated overnight at 4° C. with SP1 rabbit monoclonal Ab (ThermoScientific) diluted 1:1000 in LICOR blocking buffer/0.1% Tween-20. Wellswhich were treated with blocking buffer with Tween but no antibody wereused as a background control. Wells were washed with 0.1% Tween-20/PBSand then incubated in goat anti-rabbit IRDye™ 800 CW (LICOR Inc.;1:1000) and DRAQ5 DNA dye (1:2000 for 2 mM stock) diluted in LICORblocking buffer containing 0.1% Tween-20 and 0.01% SDS for 60 minutes.Cells were washed (50 μl/well, 5′ each) in 0.1% Tween-20/PBS. Plateswere scanned on a LICOR Odyssey infrared imaging system. Integratedintensities in the 800 nm channel and 700 nm channel were measured todetermine levels of ER and DNA respectively. Percent ER levels weredetermined as follows:(Integrated intensity 800 nm sample/integrated intensity 700 nmsample)/(Integrated intensity 800 nm untreated cells/integratedintensity 700 nm untreated cells)×100=% ER levels.

Effects on steady state levels of ER-α in additional ER+ breast cancercell lines, including BT474, CAMA1, MDA-MB-361, ZR-75-1, T47D, can beprofiled in assays similar to Example 31.

Illustrative biological data for representative compounds disclosedherein is presented in the following table:

TABLE 4 ER In-Cell Western Assay ER In-Cell Western Assay Example (SP1);IC₅₀ (SP1); Max Response  1 A +++  2 A +++  2a B +++  2b A +++  3 A +++ 3a B +++  3b A +++  4 B +++  5 A +++  6 A +++  7 A +++  8 A +++  9 A+++ 10 A +++ 11 A +++ 12 A +++ 13 A +++ 14 A +++ 15 B +++ 16 B +++ 17 A++ 18 A ++ 19 A ++ 20 A + 21 A +++ 22 A + 23 A + 24 A + 25 A + 26 A +++27 A +++ 28 A +++ A = single IC₅₀ ≦ 1 nM; B = single IC₅₀ > 1 nM + = asingle % value that is <60%; ++ = a single % value that is % ≧ 60% to<85%; +++ = a single % value that is ≧85%.

Example 32 Ishikawa Uterine Cell Alkaline Phosphatase Assay

Subconfuent Ishikawa cells in a T225 are incubated 24 hours in anestrogen free basal medium (EFBM) consisting of DMEM:Ham's F-12 50:50phenol red free basal medium containing 5% Charcoal Dextran treated FBSand 20 mM HEPES. Cells are plated the following day in EFBM in clear 384well plates at a concentration of 2.5×105 cells per mL, 16 μL per well(4000 cells per well). A 12 point semilog dilution of each compound iscarried out in DMSO and subsequently diluted in EFBM. An equal volume ofcompound in EFBM is added immediately after plating cells, and the cellsare incubated for 3 days. The cells are fixed with 5% formalin, andrinsed with PBS. Alkaline Phosphatase substrate 4-Nitrophenyl phosphatedisodium salt hexahydrate is added to a solution containing 2 mM MgCl₂,1 M diethanolamine, and adjusted to pH 9.0. The substrate solution isadded to the cell cultures (16 μL per well), and OD405 is measured in amultiwall plate spectrophotometer when the optical density at 405 nmwavelength of cells treated with 17β-estradiol in the concentrationrange of 1-30 nM reaches 1.0-1.2 absorbance units. Cells treated withDMSO alone serve as a background control. Percent activity in backgroundsubtracted samples is measured as follows: % activity=OD₄₀₅ sample/OD405max of 17β-estradiol treated cells×100.

Example 33 Ovarian Cancer Cell Viability Assays

BG-1, cells were adjusted to a concentration of 20,000 cells per mL inRPMI containing 10% FBS and 20 mM HEPES. 16 microliters of the cellsuspension (320 cells) was added to each well of a 384 well plate, andthe cells were incubated overnight to allow the cells to adhere. Thefollowing day an eleven point, serial semilog dilution of each compoundwas added to the cells in 16 μL at a final concentration ranging from0.3-0.000003 μM. After 5 days' compound exposure, 16 μL of CellTiter-GLo(Promega, Madison Wis.) was added to the cells the relative luminescenceunits (RLUs) of each well was determined. CellTiter-Glo added to 32 μLof medium without cells was used to obtain a background value. ThePercent viability of each sample was determined as follows: (RLUsample-RLU background/RLU untreated cells-RLU background)×100=%viability.

Viability effects in additional ER+ ovarian cancer cell lines, includingA1847, SKOV3, SW626, A2780, can be profiled in assays similar to Example33.

Example 34 Ovarian Cancer Cell ER-α in Cell Western Assay

BG-1 cells were adjusted to a concentration of 200,000 cells per mL inRPMI containing 10% charcoal-stripped FBS and 20 mM HEPES. 16microliters of the cell suspension (3200 cells) was added to each wellof a poly-D-lysine 384 well plate, and the cells were incubatedovernight to allow the cells to adhere. The following day an elevenpoint, serial semilog dilution of each compound was added to the cellsin 16 μL at a final concentration ranging from 0.3-0.000003 μM. At 4 or24 hr post compound addition, the cells were fixed (10% formalin in PBS)for 20 minutes. Cells were permeablized in PBS 0.1% Triton and blockedwith LICOR blocking buffer (50 μl/well, 90′). The wells were thenincubated overnight at 4° C. with ER1D5 (Santa Cruz Biotechnology)diluted 1:100 in LICOR blocking buffer/0.1% Tween-20. Wells which weretreated with blocking buffer with Tween but no antibody were used as abackground control. Wells were washed with 0.1% Tween-20/PBS and thenincubated in goat anti-mouse IRDye™ 800 CW (LICOR Inc.; 1:1000) andDRAQ5 DNA dye (1:2000 for 2 mM stock) diluted in LICOR blocking buffercontaining 0.1% Tween-20 and 0.01% SDS for 60 minutes. Cells were washed(50 μl/well, 5′ each) in 0.1% Tween-20/PBS. Plates were scanned on aLICOR Odyssey infrared imaging system. Integrated intensities in the 800nm channel and 700 nm channel were measured to determine levels of ERand DNA respectively. Percent ER levels were determined as follows:(Integrated intensity 800 nm sample/integrated intensity 700 nmsample)/(Integrated intensity 800 nm untreated cells/integratedintensity 700 nm untreated cells)×100=% ER levels.

Effects on steady state levels of ER-α in additional ER+ ovarian cancercell lines, including A1847, SKOV3, SW626, A2780, can be profiled inassays similar to Example 34.

Other cancer cell lines contemplated for testing compounds describedherein include: ER-positive endometrial cell lines (Ishikawa, ECC1,HEC-1, EnCa-101) and ER-positive cervical cell lines (Caski, HeLa,SiHa).

Example 35 PEO Cell Viability Assays

PEO-1, PEO-4 and PEO-6 ovarian cancer cell lines were adjusted to aconcentration of 20,000 cells per mL in RPMI containing 10% FBS. 16microliters of the cell suspension (320 cells) was added to each well ofa 384 well plate, and the cells were incubated overnight to allow thecells to adhere. The following day a 10 point, serial 1:5 dilution ofeach compound was added to the cells in 16 μL at a final concentrationranging from 1-0.0000005 μM. After 7 days' compound exposure, 16 μL ofCellTiter-GLo (Promega, Madison Wis.) was added to the cells therelative luminescence units (RLUs) of each well was determined.CellTiter-Glo added to 32 μL of medium without cells was used to obtaina background value. The Percent viability of each sample was determinedas follows: (RLU sample-RLU background/RLU untreated cells-RLUbackground)×100=% viability.

Example 36 PEO ER Western Analysis

Cells were plated in RPMI 5% CSS for 48 hours, then treated withcompound for 4 or 24 hours. Cells were lysed in modifiedradioimmunoprecipitation buffer (mRIPA; 10 mM Tris, 150 mM NaCl, 1%(v/v) NP-40, 0.5% deoxycholate, 0.1% SDS, 5 mM EDTA, pH 7.4) containingHalt Protease & Phosphatase Single-Use Inhibitor Cocktail (ThermoScientific, Cat. No. 78442). Total protein of the clarified lysates wasquantitated by Lowry Assay (Biorad DC protein assay). NuPAGE® LDS SampleBuffer and Sample Reducing Agent were added to the lysates and heated to70° C. for 10 mins. 15 ug of total cell protein was separatedelectrophoretically in a NuPAGE 4-12% Bis Tris Gel in MOPS SDS runningbuffer, then transferred to a nitrocellulose membrane in transfer bufferusing an XCell II blot module. Membranes were incubated in BlockingBuffer (LI-COR, Lincoln, Nebr.) for 30 minutes at room temperature,followed by 60 minute incubations with a rabbit antibody against ERalpha (SP-1, Thermo Fisher Scientific, Cat. No. RM-9101), ER beta (CellSignaling Technology, Cat. No. 5513), or mouse antibody against alphatubulin (Sigma, Cat. No. T6199). Following incubation with an IRDye®Conjugated Goat Anti Mouse or Anti Rabbit IgG (LI-COR), protein bandswere quantified using an Odyssey® Infrared Imaging System. Graphing ofdata to determine ER levels was performed using Graphpad PRISM®software. % ER levels were calculated as follows:% ER=(fluorescence ER band of sample-bkgrd/fluorescence Tubulin band ofsample-bkgrd)/(fluorescence ER band of untreatedcells-bkgrd/fluorescence Tubulin of untreated cells-bkgrd)

Example 37 Breast Cancer Model; Xenograft Assay (MCF-7)

Time release pellets containing 0.72 mg 17β Estradiol weresubcutaneously implanted into nu/nu mice. MCF-7 cells were grown in RPMIcontaining 10% FBS at 5% CO₂, 37° C. Cells were spun down andre-suspended in 50% RPMI (serum free) and 50% Matrigel at 1×10⁷cells/mL. MCF-7 cells were subcutaneously injected (100 μL/animal) onthe right flank 2-3 days post pellet implantation. Tumor volume(length×width²/2) was monitored bi-weekly. When tumors reached anaverage volume of ˜200 mm³ animals were randomized and treatment wasstarted. Animals were treated with Vehicle or Compound daily for 4weeks. Tumor volume and body weight were monitored bi-weekly throughoutthe study. At the conclusion of the treatment period, plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 38 Breast Cancer Model; Xenograft Assay (MCF-7 Derivative)

Female nu/nu mice (with supplemental 17β Estradiol pellets; 0.72 mg; 60day slow release) bearing MCF-7 tumors (mean tumor volume 200 mm³) weretreated with Tamoxifen (citrate) by oral gavage. Tumor volume(length×width²/2) and body weight were monitored twice weekly. Followinga significant anti-tumor response in which tumor volume remained static,evident tumor growth was first observed at approximately 100 days oftreatment. At 120 days of treatment, tamoxifen dose was increased.Rapidly growing tumors were deemed tamoxifen resistant and selected forin vivo passage into new host animals. Tumor Fragments (˜100 mm³/animal)from the tamoxifen resistant tumors were subcutaneously implanted intothe right flank of female nu/nu mice (with 17β Estradiol pellets (0.72mg; 60 day slow release)). Passaged tumors were maintained underconstant Tamoxifen selection, and Tumor volume (length×width²/2) wasmonitored weekly. When tumor volume reached ˜150-250 mm³, animals wererandomized into treatment groups (mean tumor volume 200 mm³) andtamoxifen treatment was terminated (except for a tamoxifen control arm).Animals were treated with Vehicle or Compound daily for 4 weeks. Tumorvolume and body weight were monitored twice weekly for the duration ofthe study. At the conclusion of the treatment period; plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 39 Ovarian Cancer Model; Xenograft Assay (BG-1)

Time release pellets (0.72 mg 17β Estradiol/60 days) were subcutaneouslyimplanted into female nu/nu mice. BG-1 cells were grown in DMEM Ham'sF-12 50/50 containing 10% FBS, 10 mM Sodium Pyruvate, 10 mMNon-Essential Amino Acids at 5% CO₂, 37° C. Cells were spun down andre-suspended in 50% DMEM Ham's F-12 (serum free) and 50% Matrigel at5×10⁷ cells/mL. BG-1 cells were subcutaneously injected (100 μL/animal)on the right flank 2-3 days post pellet implantation. Tumor volume(length×width²/2) was monitored bi-weekly. When tumors reached anaverage volume of ˜250 mm³ animals were randomized and treatment wasstarted. Animals were treated with Vehicle or Compound daily for 4weeks. Tumor volume and body weight were monitored bi-weekly throughoutthe study. At the conclusion of the treatment period; plasma and tumorsamples were taken for pharmacokinetic and pharmacodynamic analyses,respectively.

Example 40 Endometrial Cancer Model; Xenograft Assay (ECC-1)

ECC-1 cells were grown in DMEM (phenol red, 4.5 g/L glucose andL-glutamine) containing 10% FBS, 1% Non-Essential Amino Acids and 100units Penicillin/Streptomycin at 10% CO₂, 37° C. Cells were spun downand re-suspended in 50% DMEM (serum free) and 50% Matrigel (BD, highconcentration) at 5×10⁷ cells/mL. Time release pellets (0.72 mg 17-βEstradiol/60 days) were subcutaneously implanted into female nu/nu mice.ECC-1 cells were subcutaneously injected (100 μL/animal) on the rightflank 2-3 days post pellet implantation. Tumor volume was monitored andwhen tumors reached a suitable size for transplant they were excised.Excised tumors were cut into small pieces (˜100 mm³) and seriallytransplanted (10 G trocar, right flank) into female nu/nu containingestradiol pellets (0.72 mg 17-β Estradiol/60 days) for 2-3 days. Tumorvolume (length×width×width/2) was monitored and when palpable tumorswere observed, animals were randomized and treatment was started.Animals were treated with Vehicle or Compound daily for 4 weeks or untiltumor volume reached 2000 mm³ (whichever came first). Tumor volume andbody weight were monitored bi-weekly throughout the study. At theconclusion of the treatment period; plasma and tumor samples were takenfor pharmacokinetic and pharmacodynamic analyses, respectively.

Example 41 Immature Uterine Wet Weight-Antagonist Mode

Female immature CD-IGS rats (21 days old upon arrival) were treated forthree days. Animals were dosed daily for three days. Vehicle or testcompound was administered orally by gavage followed 15 minutes later byan oral dose of 0.1 mg/kg Ethynyl Estradiol. On the fourth day 24 hoursafter dose, plasma was collected for pharmacokinetic analysis.Immediately following plasma collection, the animals were euthanized andthe uterus was removed and weighed.

Example 42 Immature Uterine Wet Weight-Agonist Mode

Female immature CD-IGS rats (21 days old upon arrival) were treated forthree days. Animals were dosed daily for three days. Vehicle or testcompound was administered orally by gavage followed 15 minutes later bya second oral dose of vehicle. On the fourth day 24 hours after dose,plasma was collected for pharmacokinetic analysis. Immediately followingplasma collection, the animals were euthanized and the uterus wasremoved and weighed.

Example 43 Adult Uterine Wet Weight-10 Day

Female CD-IGS rats (69 days old, Charles River Laboratories) werepurchased and split into groups. Group 1 was ovariectomized at thevendor (Charles River Laboratories) at 60 days of age and the study wasstarted 2 weeks after surgery, while groups 2-8 were intact. Vehicle ortest compound was administered orally for 10 days. Two hours after the10^(th) and final dose, cardiac punctures were performed and serum wascollected for pharmacokinetic and estradiol analyses. Immediatelyfollowing serum collection, the animals were euthanized and the uterusand ovaries were removed and weighed. Uteri and ovaries from 2 animalsper group were fixed in 10% neutral buffered formalin and sent out to beparaffin embedded, sectioned and stained for H&E (SDPath). Stainedtissues were analyzed in house and then sent out to be read by a boardcertified pathologist. Uteri and ovaries from 4 animals per group wereflash frozen in liquid N₂ for transcriptional analysis, examining aselect set of genes modulated by the estrogen receptor.

Example 44 Breast Cancer Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, as first- orsecond-line treatment of estrogen receptor (ER) positive metastaticbreast cancer, collect information on any side effects the compound maycause, and evaluate the pharmacokinetic properties of the compound.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day.

Outcome Measures:

Primary Outcome Measures: tumor response and/or disease control.

Secondary Outcome Measures: (a) side-effects; (b) pharmacokineticproperties; (c) proportion of patients that have complete or partialresponse or stable disease at defined time points; (d) time toprogression and overall survival; and (e) biomarkers predictive ofclinical response.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day. Prior to each dosing cycle, a physical exam, blood workand assessment of any side effects will be performed. Every 12 weeks thepatient's cancer will be re-evaluated with either a CT scan or MRI todetermine whether the treatment is working. Participation in this studywill last until disease progression or unacceptable toxicity.

Eligibility:

Female subjects that are 18 years and older.

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of invasive breastcancer, stage 1V disease; at least one measurable target lesion asdefined by RECIST that has not been previously treated with localtherapy; post-menopausal status; ER positive breast cancer;HER2-negative breast cancer; up to one prior hormonal therapy foradvanced or metastatic disease; ECOG performance status 0-1; lifeexpectancy>12 weeks; adequate liver and bone marrow function:AST<2.5×ULN; Bilirubin<1.5×ULN; ANC>1,500/ul; platelet count>100,000/ul;normal PT and PTT; at least 2 weeks since prior radiation and recoveredfrom treatment-related toxicity.

Exclusion Criteria:

HER2-positive breast cancer; prior chemotherapy regimen for metastaticdisease; history of, or presence of brain metastases; concurrentinvestigational drug treatment; prior bone marrow or stem celltransplant; history of other malignancy within the last 5 years, notincluding curatively-treated carcinoma in situ of the cervix ornon-melanoma skin cancer; uncontrolled infection; active bleeding, orhistory of bleeding requiring transfusion; active cardiac disease;serious medical or psychiatric illness.

Example 45 Endometrial Carcinoma Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, in the treatment of advanced or metastaticendometrial carcinoma, collect information on any side effects thecompound may cause, and evaluate the pharmacokinetic properties of thecompound.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day.

Outcome Measures:

Primary Outcome Measures: tumor response and/or disease controlSecondary Outcome Measures: (a) side-effects; (b) pharmacokineticproperties; (c) proportion of patients that have complete or partialresponse or stable disease at defined time points; (d) time toprogression and overall survival; and (e) biomarkers predictive ofclinical response.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day. Prior to each dosing cycle, a physical exam, blood workand assessment of any side effects will be performed. Every 12 weeks thepatient's cancer will be re-evaluated with either a CT scan or MRI todetermine whether the treatment is working. Participation in this studywill last until disease progression or unacceptable toxicity.

Eligibility:

Female subjects that are 18 years and older.

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of advanced ormetastatic endometrial carcinoma; at least one measurable target lesionas defined by RECIST that has not been previously treated with localtherapy; hormone receptor positive endometrial carcinoma; ECOGperformance status 0-1; life expectancy>12 weeks; adequate liver andbone marrow function: AST<2.5×ULN; Bilirubin<1.5×ULN; ANC>1,500/ul;platelet count>100,000/ul; normal PT and PTT; at least 2 weeks sinceprior radiation and recovered from prior surgery or treatment-relatedtoxicity.

Exclusion Criteria:

History of, or presence of brain metastases; concurrent investigationaldrug treatment; prior bone marrow or stem cell transplant; history ofother malignancy within the last 5 years, not includingcuratively-treated carcinoma in situ of the cervix or non-melanoma skincancer; uncontrolled infection; active bleeding, or history of bleedingrequiring transfusion; active cardiac disease; serious medical orpsychiatric illness.

Example 46 Ovarian Cancer Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, in the treatment of advanced ovarian cancer,collect information on any side effects the compound may cause, andevaluate the pharmacokinetic properties of the compound.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day.

Outcome Measures:

Primary Outcome Measures: tumor response and/or disease control

Secondary Outcome Measures: (a) side-effects; (b) pharmacokineticproperties; (c) proportion of patients that have complete or partialresponse or stable disease at defined time points; (d) time toprogression and overall survival; and (e) biomarkers predictive ofclinical response.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day. Prior to each dosing cycle, a physical exam, blood work(including tumor markers, e.g., CA-125) and assessment of any sideeffects will be performed. Every 12 weeks the patient's cancer will bere-evaluated with either a CT scan or MRI to determine whether thetreatment is working. Participation in this study will last untildisease progression or unacceptable toxicity.

Eligibility:

Female subjects that are 18 years and older.

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of advanced ovariancancer; at least one measurable target lesion as defined by RECIST thathas not been previously treated with local therapy; ER positive ovariancancer; ECOG performance status 0-1; life expectancy>12 weeks; adequateliver and bone marrow function: AST<2.5×ULN; Bilirubin<1.5×ULN;ANC>1,500/ul; platelet count>100,000/ul; normal PT and PTT; at least 2weeks since prior radiation and recovered from prior surgery ortreatment-related toxicity.

Exclusion Criteria:

History of, or presence of brain metastases; concurrent investigationaldrug treatment; prior bone marrow or stem cell transplant; history ofother malignancy within the last 5 years, not includingcuratively-treated carcinoma in situ of the cervix or non-melanoma skincancer; uncontrolled infection; active bleeding, or history of bleedingrequiring transfusion; active cardiac disease; serious medical orpsychiatric illness.

Example 47 ER-Positive NSCLC Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, as single agent or in combination in thetreatment of advanced or metastatic estrogen receptor (ER) positivenon-small cell lung cancer (NSCLC), collect information on any sideeffects the compound may cause as single agent or in combination, andevaluate the pharmacokinetic properties of the compound as single agentor in combination.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day as single agent or in combination.

Outcome Measures:

Primary Outcome Measures: tumor response and/or disease control.Secondary Outcome Measures: (a) side-effects; (b) pharmacokineticproperties; (c) proportion of patients that have complete or partialresponse or stable disease at defined time points; (d) time toprogression and overall survival; and (e) biomarkers predictive ofclinical response.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day as single agent or in combination. Prior to each dosingcycle, a physical exam, blood work and assessment of any side effectswill be performed. Every 12 weeks the patient's cancer will bere-evaluated with either a CT scan or MRI to determine whether thetreatment is working. Participation in this study will last untildisease progression or unacceptable toxicity.

Eligibility:

Male and female subjects that are 18 years and older.

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of advanced ormetastatic ER-positive NSCLC; at least one measurable target lesion asdefined by RECIST that has not been previously treated with localtherapy; ECOG performance status 0-1; life expectancy>12 weeks; adequateliver and bone marrow function: AST<2.5×ULN; Bilirubin<1.5×ULN;ANC>1,500/ul; platelet count>100,000/ul; normal PT and PTT; at least 2weeks since prior radiation and recovered from prior surgery ortreatment-related toxicity.

Exclusion Criteria:

History of, or presence of brain metastases; concurrent investigationaldrug treatment; prior bone marrow or stem cell transplant; history ofother malignancy within the last 5 years, not includingcuratively-treated carcinoma in situ of the cervix or non-melanoma skincancer; uncontrolled infection; active bleeding, or history of bleedingrequiring transfusion; active cardiac disease; serious medical orpsychiatric illness.

Example 48 Endometriosis Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, as single agent or in combination in thetreatment of patients with symptomatic/severe endometriosis, collectinformation on any side effects the compound may cause as single agentor in combination, and evaluate the pharmacokinetic properties of thecompound as single agent or in combination.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day as single agent or in combination.

Outcome Measures:

The outcome measures of this study are symptoms improvement and/or painrelief and shrinkage of endometrial tissue.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day as single agent or in combination. Prior to each dosingcycle, a physical exam, blood work and assessment of any side effectswill be performed.

Eligibility:

Female subjects that are 18 years and older.

Inclusion Criteria:

Diagnosis of symptomatic endometriosis; pre- or peri-menopausal status;ECOG performance status 0-1; adequate liver and bone marrow function:AST<2.5×ULN; Bilirubin<1.5×ULN; ANC>1,500/ul; platelet count>100,000/ul;normal PT and PTT; at least 2 weeks since prior surgery ortreatment-related toxicity.

Exclusion Criteria:

Pregnancy or lactating; history of other malignancy within the last 5years, not including curatively-treated carcinoma in situ of the cervixor non-melanoma skin cancer; concurrent investigational drug treatment;uncontrolled infection; active cardiac disease; aerious medical orpsychiatric illness.

Example 49 Uterine Leiomyoma Clinical Trial

Purpose:

The purposes of this study are to assess the efficacy of a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, as single agent or in combination in thetreatment of patients with symptomatic uterine leiomyoma, collectinformation on any side effects the compound may cause as single agentor in combination, and evaluate the pharmacokinetic properties of thecompound as single agent or in combination.

Intervention:

Patients are administered 1-50 mg/kg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, per day or twice a day as single agent or in combination.

Outcome Measures:

The outcome measures of this study are symptoms improvement and/or painrelief and shrinkage of leiomyomas.

Detailed Description:

Patients will be given a compound of Formula (I), (II), (III), (IV),(V), or (VI), or a pharmaceutically acceptable salt thereof, orally onceor twice a day as single agent or in combination. Prior to each dosingcycle, a physical exam, blood work and assessment of any side effectswill be performed.

Eligibility:

Female subjects that are 18 years and older.

Inclusion Criteria:

Diagnosis of symptomatic uterine leiomyoma; pre- or peri-menopausalstatus; ECOG performance status 0-1; adequate liver and bone marrowfunction: AST<2.5×ULN; Bilirubin<1.5×ULN; ANC>1,500/ul; plateletcount>100,000/ul; normal PT and PTT; at least 2 weeks since priorsurgery or treatment-related toxicity.

Exclusion Criteria:

Pregnancy or lactating; history of other malignancy within the last 5years, not including curatively-treated carcinoma in situ of the cervixor non-melanoma skin cancer; concurrent investigational drug treatment;uncontrolled infection; active cardiac disease; serious medical orpsychiatric illness.

Example 50 Parenteral Pharmaceutical Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection (subcutaneous, intravenous), 100 mg of awater-soluble compound of Formula (I), (II), (III), (IV), (V), or (VI),or pharmaceutically acceptable salt thereof, is dissolved in sterilewater and then mixed with 10 mL of 0.9% sterile saline. The mixture isincorporated into a dosage unit form suitable for administration byinjection

In another embodiment, the following ingredients are mixed to form aninjectable formulation: 1.2 g of a compound of Formula (I), (II), (III),(IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, 2.0mL of sodium acetate buffer solution (0.4 M), HCl (1 N) or NaOH (1 M)(q.s. to suitable pH), water (distilled, sterile) (q.s. to 20 mL). Allof the above ingredients, except water, are combined and stirred and ifnecessary, with slight heating if necessary. A sufficient quantity ofwater is then added.

Example 51 Oral Solution

To prepare a pharmaceutical composition for oral delivery, an aqueous20% propylene glycol solution is prepared. To this is added a sufficientamount of a compound of Formula (I), (II), (III), (IV), (V), or (VI), ora pharmaceutically acceptable salt thereof, to provide a 20 mg/mLsolution.

Example 52 Oral Capsule

To prepare a pharmaceutical composition for oral delivery, 100-500 mg ofa compound of Formula (I), (II), (III), (IV), (V), or (VI), or apharmaceutically acceptable salt thereof, is mixed with starch. Themixture is incorporated into an oral dosage unit such as a hard gelatincapsule, which is suitable for oral administration.

In another embodiment, 100-500 mg of a compound of Formula (I), (II),(III), (IV), (V), or (VI), or a pharmaceutically acceptable saltthereof, is placed into Size 4 capsule, or size 1 capsule (hypromelloseor hard gelatin) and the capsule is closed.

Example 53 Oral Tablet

A tablet is prepared by mixing 48% by weigh of a compound of Formula(I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptablesalt thereof, 45% by weight of microcrystalline cellulose, 5% by weightof low-substituted hydroxypropyl cellulose, and 2% by weight ofmagnesium stearate. Tablets are prepared by direct compression. Thetotal weight of the compressed tablets is maintained at 250-500 mg.

Example 54 Topical Gel Composition

To prepare a pharmaceutical topical gel composition, a compound ofFormula (I), (II), (III), (IV), (V), or (VI), or a pharmaceuticallyacceptable salt thereof, is mixed with hydroxypropyl celluose, propyleneglycol, isopropyl myristate and purified alcohol USP. The resulting gelmixture is then incorporated into containers, such as tubes, which aresuitable for topical administration.

The examples and embodiments described herein are for illustrativepurposes only and various modifications or changes suggested to personsskilled in the art are to be included within the spirit and purview ofthis application and scope of the appended claims.

What is claimed is:
 1. A compound of Formula (II), or a pharmaceuticallyacceptable salt, or solvate thereof:

wherein, R¹ is H, C₁-C₆alkyl, or C₁-C₆fluoroalkyl;

R²³ is —CH₂F; t is 1; R⁵ is H, halogen, —CN, —OH, —OR¹¹, —NHR¹¹,—NR¹¹R¹², SR¹¹, —S(═O)R¹², —S(O)₂R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl,C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, or C₁-C₆heteroalkyl; each R⁶ isindependently selected from H, halogen, —CN, —OH, —OR¹¹, —SR¹¹,—S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, and C₁-C₆heteroalkyl; each R¹⁰ is independently selectedfrom H, halogen, —CN, —OH, —OR¹¹, —SR¹¹, —S(═O)R¹², —S(═O)₂R¹²,C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy, C₁-C₆alkoxy, andC₁-C₆heteroalkyl; each R¹¹ is independently selected from H, —C(═O)R¹²,—C(═O)OR¹², —C(═O)NHR¹², C₁-C₆alkyl, C₁-C₆heteroalkyl, C₁-C₆fluoroalkyl,substituted or unsubstituted C₃-C₁₀cycloalkyl, substituted orunsubstituted C₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —C₁-C₂alkylene-(substituted orunsubstituted C₃-C₁₀cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted aryl), and —C₁-C₂alkylene-(substituted or unsubstitutedheteroaryl); each R¹² is independently selected from substituted orunsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆heteroalkyl,substituted or unsubstituted C₁-C₆fluoroalkyl, substituted orunsubstituted C₃-C₁₀cycloalkyl, substituted or unsubstitutedC₂-C₁₀heterocycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, —C₁-C₂alkylene-(substituted orunsubstituted C₃-C₁₀cycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted C₂-C₁₀heterocycloalkyl), —C₁-C₂alkylene-(substituted orunsubstituted aryl), and —C₁-C₂alkylene-(substituted or unsubstitutedheteroaryl); m is 0, 1, 2, 3 or 4; and n is 0, 1, or
 2. 2. The compoundof claim 1, or a pharmaceutically acceptable salt, or solvate thereof,wherein: R¹ is H or C₁-C₆alkyl.
 3. The compound of claim 2, or apharmaceutically acceptable salt, or solvate thereof, wherein: R⁵ is—OH; each R¹⁰ is independently selected from H, halogen, —CN, —OH,—S(═O)R¹², —S(═O)₂R¹², C₁-C₆alkyl, C₁-C₆fluoroalkyl, C₁-C₆fluoroalkoxy,C₁-C₆alkoxy, and C₁-C₆heteroalkyl; and R¹¹ is H.
 4. The compound ofclaim 3, or a pharmaceutically acceptable salt, or solvate thereof,wherein: R¹ is H, or —CH₃.
 5. The compound of claim 1, or apharmaceutically acceptable salt, or solvate thereof, wherein thecompound has one of the following structures:


6. The compound of claim 5, or a pharmaceutically acceptable salt, orsolvate thereof, wherein: R⁵ is —OH; each R⁶ is independently selectedfrom H and halogen; each R¹⁰ is independently selected from H andhalogen; and R¹¹ is H.
 7. The compound of claim 6, or a pharmaceuticallyacceptable salt, or solvate thereof, wherein:


8. The compound of claim 6, or a pharmaceutically acceptable salt, orsolvate thereof, wherein:


9. The compound of claim 1, wherein the compound has one of thefollowing structures:

or a pharmaceutically acceptable salt, or solvate thereof.
 10. Thecompound of claim 1, wherein the compound has one of the followingstructures:

or a pharmaceutically acceptable salt, or solvate thereof.
 11. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt, or solvate thereof, and at least onepharmaceutically acceptable inactive ingredient.
 12. The pharmaceuticalcomposition of claim 11, wherein the pharmaceutical composition isformulated for intravenous injection, subcutaneous injection, oraladministration, or topical administration.
 13. The pharmaceuticalcomposition of claim 11, wherein the pharmaceutical composition is atablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion,a solution, an emulsion, an ointment, or a lotion.
 14. A method fortreating cancer in a mammal comprising administering to the mammal acompound of claim 1, or a pharmaceutically acceptable salt, or solvatethereof, wherein the cancer is breast cancer, cervical cancer,colorectal cancer, lung cancer, ovarian cancer, endometrial cancer,prostate cancer, or uterine cancer.